Antiviral therapeutic agents

ABSTRACT

The invention provides compounds of Formula I: 
     
       
         
         
             
             
         
       
     
     as described herein, as well as pharmaceutical compositions comprising the compounds, and synthetic methods and intermediates that are useful for preparing the compounds. The compounds of Formula (I) are useful as anti-viral agents and/or as anti-cancer agents.

RELATED APPLICATIONS

This patent application is a continuation of U.S. application Ser. No.12/398,866, filed Mar. 5, 2009 and claims the benefit of priority ofU.S. Application No. 61/034,053 filed Mar. 5, 2008, and of U.S.Application No. 61/079,370, filed Jul. 9, 2008, which applications areherein incorporated by reference.

BACKGROUND OF THE INVENTION

Viral diseases are a major cause of death and economic loss in theworld. The Flaviviridae family of viruses consists of three genera: theflaviviruses (including dengue, West Nile, and yellow fever viruses),hepatitis virus (HCV), and the pestiviruses (including bovine viraldiarrhea virus, BVDV). The disease states and conditions caused bymembers of this family include yellow fever, dengue, Japaneseencephalitis, St. Louis encephalitis, Hepatitis B and C, West Niledisease, and AIDS. Currently, human immunodeficiency virus (HIV),hepatitis B virus (HBV) and hepatitis C virus (HCV) infections areresponsible for the largest number of viral related deaths worldwide.Although there are some drugs useful for treating HIV, there are only afew drugs useful for treating HBV, and no drugs that are broadly usefulfor treating HCV.

Ribavirin (1-β-D-ribofuranosyl-1-1,2,4-triazole-3-carboxamide) is asynthetic, non-interferon-inducing, broad spectrum antiviral nucleoside.Ribavirin is structurally similar to guanosine, and has in vitroactivity against several DNA and RNA viruses including Flaviviridae(Davis. Gastroenterology 118:S104-S114, 2000). Ribavirin reduces serumamino transferase levels to normal in 40% of patients, but it does notlower serum levels of HCV-RNA (Davis. Gastroenterology 118:S104-S114,2000). Thus, ribavirin alone is not effective in reducing viral RNAlevels. Additionally, ribavirin has significant toxicity and is known toinduce anemia.

Interferons (IFNs) are compounds which have been commercially availablefor the treatment of chronic hepatitis for nearly a decade. IFNs areglycoproteins produced by immune cells in response to viral infection.IFNs inhibit viral replication of many viruses, including HCV. When usedas the sole treatment for hepatitis C infection, IFN suppresses serumHCV-RNA to undetectable levels. Additionally, IFN normalizes serum aminotransferase levels. Unfortunately, the effects of IFN are temporary anda sustained response occurs in only 8%-9% of patients chronicallyinfected with HCV (Davis. Gastroenterology 118:S104-S114, 2000).

HCV is a positive stranded ss RNA virus with a well characterizedRNA-dependent RNA polymerase (RdRp) and a well characterized diseaseprogression. HCV has infected an estimated 170 million people worldwide,leading to a major health crisis as a result of the disease. Indeed,during the next few years the number of deaths from HCV-related liverdisease and hepatocellular carcinoma may overtake those caused by AIDS.Egypt is the hardest hit country in the world, with 23% of thepopulation estimated to be carrying the virus; whereas, in the USA theprevalence of chronic infections has recently been determined to bearound 1.87% (2.7 million persons). HCV infections become chronic inabout 50% of cases. Of these, about 20% develop liver cirrhosis that canlead to liver failure, including hepatocellular carcinoma.

The NS5B region of HCV encodes a 65 KDa RdRp thought to be responsiblefor viral genome replication. RdRps function as the catalytic subunit ofthe viral replicase required for the replication of all positive-strandviruses. The NS5B protein has been well characterized, shown to possessthe conserved GDD motif of RdRps and in vitro assay systems have beenreported. Cellular localization studies revealed that NS5B ismembrane-associated in the endoplasmic reticulum like NS5A, suggestingthat those two proteins may remain associated with one another afterproteolytic processing. Additional evidence suggests that NS3, NS4A andNS5B interact with each other to form a complex that functions as partof the replication machinery of HCV.

The X-ray crystal structure of NS5B apoenzyme has been determined andthree very recent publications describe the unusual shape of themolecule. This unique shape for a polymerase, resembling a flat sphere,is attributed to extensive interactions between the fingers and thumbsubdomains in such a way that the active site is completely encircled,forming a cavity 15 Å across and 20 Å deep. Modeling studies showed thatthe NS5B apoenzyme can accommodate the template-primer without largemovement of the subdomains, suggesting that the structure is preservedduring the polymerization reaction. The RdRp polypeptides from variousmembers of the Flaviviridae family and other viral families have beenshown to be conserved (J. A. Bruenn, Nucleic Acids Research, Vol. 19,No. 2 p. 217, 1991).

Currently, there are no safe and effective therapeutic agents on themarket that target HCV polymerase. There is currently a need fortherapeutic agents and therapeutic methods that are useful for treatingviral infections, such as HCV, HIV, and HBV.

In addition, there is also a current need for therapeutic agents andtherapeutic methods that are useful for treating cancer. Even thoughsignificant advances have occurred in the treatment of cancer, it stillremains a major health concern. It has been reported that cancer is thecause of death of up to one of every four Americans. Notwithstanding theadvances in treatments for cancer and other diseases there is still aneed for novel drugs that are effective to treat cancer.

SUMMARY OF THE INVENTION

The present invention provides compounds that are inhibitors of viralRNA and DNA polymerases (e.g. polymerases from hepatitis B, hepatitis C,human immunodeficiency virus, Polio, Coxsackie A and B, Rhino, Echo,small pox, Ebola, and West Nile virus) and that are useful for treatingHCV, as well as other viral infections (e.g. flaviviral infections), andcancer.

Accordingly, the invention provides a novel compound of Formula I asdescribed herebelow, or a pharmaceutically acceptable salt or prodrugthereof.

The invention also provides a pharmaceutical composition comprising acompound of Formula I, or a pharmaceutically acceptable salt or prodrugthereof, and a pharmaceutically acceptable carrier. The composition canoptionally comprise one or more additional anti-viral or anti-canceragents.

The invention also provides a method for treating a viral infection inan animal comprising administering to the animal an effective amount ofa compound of Formula I, or a pharmaceutically acceptable salt orprodrug thereof.

The invention also provides a method for inhibiting a viral RNA or DNApolymerase comprising contacting the polymerase (in vitro or in vivo)with an effective inhibitory amount of a compound of Formula I, or apharmaceutically acceptable salt or prodrug thereof.

The invention also provides a method for treating cancer in an animalcomprising administering to the animal an effective amount of a compoundof Formula I, or a pharmaceutically acceptable salt or prodrug thereof.

The invention also provides a compound of Formula I, or apharmaceutically acceptable salt or prodrug thereof, for use in medicaltherapy (e.g. for use in treating a viral infection or for use intreating cancer).

The invention also provides the use of a compound of Formula I, or apharmaceutically acceptable salt or prodrug thereof, to prepare amedicament useful for treating a viral infection in an animal (e.g. ahuman).

The invention also provides the use of a compound of Formula I, or apharmaceutically acceptable salt or prodrug thereof, to prepare amedicament useful for treating cancer in an animal (e.g. a human).

The invention also provides a compound of Formula I, or apharmaceutically acceptable salt or prodrug thereof, for theprophylactic or therapeutic treatment of a viral infection.

The invention also provides a compound of Formula I, or apharmaceutically acceptable salt or prodrug thereof, for theprophylactic or therapeutic treatment of cancer.

The invention also provides novel synthetic intermediates and syntheticmethods that are disclosed herein as being useful for preparingcompounds of Formula I, or a salt or prodrug thereof. Some compounds ofFormula I may be useful as synthetic intermediates for preparing othercompounds of Formula I.

DETAILED DESCRIPTION OF THE INVENTION Definitions

The term “pharmaceutically acceptable salt” as used herein refers to acompound of the present disclosure derived from pharmaceuticallyacceptable bases, inorganic or organic acids. Examples of suitable acidsinclude, but are not limited to, hydrochloric, hydrobromic, sulfuric,nitric, perchloric, fumaric, maleic, phosphoric, glycolic, lactic,salicyclic, succinic, toluene-p-sulfonic, tartaric, acetic, citric,methanesulfonic, formic, benzoic, malonic, naphthalene-2-sulfonic,trifluoroacetic and benzenesulfonic acids. Salts derived fromappropriate bases include, but are not limited to, alkali such as sodiumand ammonia.

The terms “treat”, “treating” and “treatment” as used herein includeadministering a compound prior to the onset of clinical symptoms of adisease state/condition so as to prevent any symptom, as well asadministering a compound after the onset of clinical symptoms of adisease state/condition so as to reduce or eliminate any symptom, aspector characteristic of the disease state/condition. Such treating need notbe absolute to be useful.

The term “animal” as used herein refers to any animal, includingmammals, such as, but not limited to, mice, rats, other rodents,rabbits, dogs, cats, swine, cattle, sheep, horses, and primates. In onespecific embodiment of the invention the animal is a human.

The term “therapeutically effective amount”, in reference to treating adisease state/condition, refers to an amount of a compound either aloneor as contained in a pharmaceutical composition that is capable ofhaving any detectable, positive effect on any symptom, aspect, orcharacteristics of a disease state/condition when administered as asingle dose or in multiple doses. Such effect need not be absolute to bebeneficial.

The term “alkyl” as used herein refers to alkyl groups having from 1 to6 carbon atoms. This term is exemplified by groups such as methyl,ethyl, n-propyl, iso-propyl, n-butyl, t-butyl, n-pentyl and the like. Ina specific embodiment, the alkyl groups have from 1-4 carbon atoms andare referred to as lower alkyl.

The term “substituted alkyl” as used herein refers to an alkyl grouphaving from 1 to 3 substituents, said substituents being selected fromthe group consisting of alkoxy, alkoxyalkyl, tri(C₁-C₄alkyl)silyl,substituted alkoxy, acyl, substituted acyl, acylamino, acyloxy, oxyacyl,amino, substituted amino, aminoacyl, aryl, substituted aryl, aryloxy,substituted aryloxy, cyano, halogen, hydroxyl, nitro, N₃, carboxyl,carboxyl esters, thiol, thioalkyl, substituted thioalkyl, thioaryl,substituted thioaryl, thioheteroaryl, substituted thioheteroaryl,thiocycloalkyl, substituted thiocycloallyl, thioheterocyclic,substituted thioheterocyclic, cycloalkyl, substituted cycloalkyl,heteroaryl, substituted heteroaryl, heterocyclic, and substitutedheterocyclic. In one specific embodiment of the invention, the term“substituted alkyl” refers to an alkyl group substituted with 1 to 3substituents, said substituents being selected from the group consistingof alkoxy, alkoxyalkyl, tri(C₁-C₄alkyl)silyl, acyl, acylamino, acyloxy,oxyacyl, amino, aminoacyl, aryl, aryloxy, cyano, halogen, hydroxyl,nitro, N₃, carboxyl, carboxyl esters, thiol, thioalkyl, thioaryl,thioheteroaryl, thiocycloalkyl, thioheterocyclic, cycloalkyl,heteroaryl, and heterocyclic.

The terms “alkenyl” or “alkene” as used herein refers to an alkenylgroup having from 2 to 10 carbon atoms and having at least 1 site ofalkenyl unsaturation. Such groups are exemplified by vinyl(ethen-1-yl),allyl, but-3-en-1-yl, and the like.

The term “substituted alkenyl” as used herein refers to alkenyl groupshaving from 1 to 3 substituents, said substituents being selected fromthose describe above for a substituted alkyl. The term “alkynyl” or“alkyne” as used herein refers to an alkynyl group having from 2-10carbon atoms and having at least 1 site of alkynyl unsaturation. Suchgroups are exemplified by, but not limited to, ethyn-1-yl, propyn-1-yl,propyn-2-yl, 1-methylprop-2-yn-1-yl, butyn-1-yl, butyn-2-yl, butyn-3-yl,and the like.

The term “substituted alkynyl” as used herein refers to alkynyl groupshaving from 1 to 3 substituents, said substituents being selected thosedescribe above for a substituted alkyl.

The term “alkoxy” refers to the group alkyl-O—.

The term “substituted alkoxy” as used herein refers to the groupsubstituted alkyl-O—.

The term “acyl” as used herein refers to the groups alkyl-C(O)—,alkenyl-C(O) alkynyl-C(O)—, cycloalkyl-C(O)—, aryl-C(O)—,heteroaryl-C(O)—, and heterocyclic-C(O).

The term “substituted acyl” as used herein refers to the groupssubstituted alkyl-C(O)—, substituted alkenyl-C(O)—, substitutedalkynyl-C(O)—, substituted cycloalkyl-C(O)—, substituted aryl-C(O)—,substituted heteroaryl-C(O), and substituted heterocyclic-C(O)—.

The term “acylamino” as used herein refers to the group-C(O)NZ₁Z₂ whereeach Z₁ and Z₂ are independently selected from the group consisting ofhydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl,alkynyl and substituted alkynyl, and the substituents described above inthe definition of substituted alkyl.

The term “acyloxy” as used herein refers to the groups alkyl-C(O)O—,substituted alkyl-C(O)O—, alkenyl-C(O)O—, substituted alkenyl-C(O)O—,alkynyl-C(O)O—, substituted alkynyl-C(O)O—, aryl-C(O)O—, substitutedaryl-C(O)O—, cycloalkyl-C(O)O—, substituted cycloalkyl-C(O)O—,heteroaryl-C(O)O—, substituted heteroaryl-C(O)O—, heterocyclic-C(O)O—,and substituted heterocyclic-C(O)O—.

The term “oxyacyl” as used herein refers to the groups alkyl-OC(O)—,substituted alkyl-OC(O)—, alkenyl-OC(O)—, substituted alkenyl-OC(O)—,alkynyl-OC(O)—, substituted alkynyl-OC(O)—, aryl-OC(O)—, substitutedaryl-OC(O)—, cycloalkyl-OC(O)—, substituted cycloalkyl-OC(O)—,heteroaryl-OC(O)—, substituted heteroaryl-OC(O)—, heterocyclic-OC(O)—,and substituted heterocyclic-OC(O)—.

The term “amino” as used herein refers to the group —NH₂.

The term “substituted amino” as used herein refers to the group —NZ₁Z₂where Z₁ and Z₂ are as described above in the definition of acylamino,provided that Z₁ and Z₂ are both not hydrogen.

The term “aminoacyl” as used herein refers to the groups —NZ₃C(O)alkyl,—NZ₃C(O)substituted alkyl, —NZ₃C(O)cycloalkyl, —NZ₃C(O)substitutedcycloalkyl, —NZ₃C(O)alkenyl, —NZ₃C(O) substituted alkenyl,—NZ₃C(O)alkynyl, —NZ₃C(O) substituted alkynyl, —NZ₃C(O)aryl, —NZ₃C(O)substituted aryl, —NZ₃C(O)heteroaryl, —NZ₃C(O) substituted heteroaryl,—NZ₃C(O)heterocyclic, and —NZ₃C(O) substituted heterocyclic, where Z₃ ishydrogen or alkyl.

The term “aryl” as used herein refers to a monovalent aromatic cyclicgroup of from 6 to 14 carbon atoms having a single ring (e.g., phenyl)or multiple condensed rings (e.g., naphthyl or anthryl) which condensedrings may or may not be aromatic. Exemplary aryls include, but are notlimited to, phenyl and naphthyl.

The term “substituted aryl” as used herein refers to aryl groups whichare substituted with from 1 to 3 substituents selected from alkyl,substituted alkyl, alkenyl, substituted alkenyl, alkynyl and substitutedalkynyl, and those substituents described above in the definition ofsubstituted alkyl.

The term “aryloxy” as used herein refers to the group aryl-O— thatincludes, by way of example but not limitation, phenoxy, naphthoxy, andthe like.

The term “substituted aryloxy” as used herein refers to substitutedaryl-O-groups.

The term “carboxyl” as used herein refers to —COOH or salts thereof.

The term “carboxyl esters” as used herein refers to thegroups-C(O)O-alkyl, —C(O)O-substituted alkyl, —C(O)O-aryl, and—C(O)O-substituted aryl.

The term “cycloalkyl” as used herein refers to a saturated orunsaturated cyclic hydrocarbon ring systems, such as those containing 1to 3 rings and 3 to 7 carbons per ring. Exemplary groups include but arenot limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl, and adamantyl.

The term “substituted cycloalkyl” as used herein refers to a cycloalkylhaving from 1 to 5 substituents selected from the group consisting ofoxo (═O), thioxo (═S), alkyl, substituted alkyl, and those substituentsdescribed in the definition of substituted alkyl.

The term “cycloalkoxy” as used herein refers to —O-cycloalkyl groups.

The term “substituted cycloalkoxy” as used herein refers to—O-substituted cycloalkyl groups.

The term “formyl” as used herein refers to HC(O)—.

The term “halogen” as used herein refers to fluoro, chloro, bromo andiodo.

The term “heteroaryl” as used herein refers to an aromatic group of from1 to 10 carbon atoms and 1 to 4 heteroatoms selected from the groupconsisting of oxygen, nitrogen, sulfur in the ring. The sulfur andnitrogen heteroatoms atoms may also be present in their oxidized forms.Such heteroaryl groups can have a single ring (e.g., pyridyl or furyl)or multiple condensed rings (e.g., indolizinyl or benzothienyl) whereinthe condensed rings may or may not be aromatic and/or contain aheteroatom. Exemplary heteroaryl groups include, but are not limited to,heteroaryls include pyridyl, pyrrolyl, thienyl, indolyl, thiophenyl, andfuryl.

The term “substituted heteroaryl” as used herein refers to heteroarylgroups that are substituted with from 1 to 3 substituents selected fromthe same group of substituents defined for substituted aryl.

The term “heteroaryloxy” as used herein refers to the group—O-heteroaryl.

The term “substituted heteroaryloxy” as used herein refers to the group—O-substituted heteroaryl.

The term “heterocycle” or “heterocyclic” or “heterocycloalkyl” refers toa saturated or unsaturated group (but not heteroaryl) having a singlering or multiple condensed rings, from 1 to 10 carbon atoms and from 1to 4 hetero atoms selected from the group consisting of nitrogen,oxygen, sulfur, within the ring wherein, in fused ring systems, one ormore the rings can be cycloalkyl, aryl or heteroaryl provided that thepoint of attachment is through the heterocyclic ring. The sulfur andnitrogen heteroatoms atoms may also be present in their oxidized forms.

The term “substituted heterocycle” or “substituted heterocyclic” or“substituted heterocycloalkyl” refers to heterocycle groups that aresubstituted with from 1 to 3 of the same substituents as defined forsubstituted aryl.

Examples of heterocycles and heteroaryls include, but are not limitedto, azetidine, pyrrole, imidazole, pyrazole, pyridine, pyrazine,pyrimidine, pyridazine, indolizine, isoindole, indole, dihydroindole,indazole, purine, quinolizine, isoquinoline, quinoline, phthalazine,naphthylpyridine, quinoxaline, quinazoline, cinnoline, pteridine,carbazole, carboline, phenanthridine, acridine, phenanthroline,isothiazole, phenazine, isoxazole, phenoxazine, phenothiazine,imidazolidine, imidazoline, piperidine, piperazine, indoline,phthalimide, 1,2, 3,4-tetrahydroisoquinoline,4,5,6,7-tetrahydrobenzo[b]thiophene, thiazole, thiazolidine, thiophene,benzo[b]thiophene, morpholinyl, thiomorpholinyl (also referred to asthiamorpholinyl), piperidinyl, pyrrolidine, tetrahydrofuranyl, and thelike.

The term “heterocyclyloxy” as used herein refers to the group—O-heterocyclic.

The term “substituted heterocyclyloxy” as used herein refers to thegroup-O-substituted heterocyclic.

The term “phosphate” as used herein refers to the groups —OP(O)(OH)₂(monophosphate or phospho), —OP(O)(OH)OP(O)(OH)₂ (diphosphate ordiphospho) and —OP(O)(OH)OP(O)(OH)OP(O)(OH)₂ (triphosphate ortriphospho) or salts thereof including partial salts thereof. It isunderstood that the initial oxygen of the mono-, di-, and triphosphatemay include the oxygen atom of a sugar.

The term “phosphate esters” as used herein refers to the mono-, di- andtri-phosphate groups described above wherein one or more of the hydroxylgroups is replaced by an alkoxy group.

The term “phosphonate” refers to the groups —OP(O)(Z₄)(OH) or —OP(O)(Z₄)(OZ₄) or salts thereof including partial salts thereof, wherein eachZ₄ is independently selected from hydrogen, alkyl, substituted alkyl,carboxylic acid, and carboxyl ester. It is understood that the initialoxygen of the phosphonate may include the oxygen of a sugar.

The term “thiol” as used herein refers to the group —SH.

The term “thioalkyl” or “alkylthioether” or “thioalkoxy” refers to thegroup —S-alkyl.

The term “substituted thioalkyl” or “substituted alkylthioether” or“substituted thioalkoxy” refers to the group —S-substituted alkyl.

The term “thiocycloalkyl” as used herein refers to the group—S-cycloalkyl.

The term “substituted thiocycloalkyl” as used herein refers to the group—S-substituted cycloalkyl.

The term “thioaryl” as used herein refers to the group —S-aryl.

The term “substituted thioaryl” as used herein refers to thegroup-S-substituted aryl.

The term “thioheteroaryl” as used herein refers to the group—S-heteroaryl.

The term “substituted thioheteroaryl” as used herein refers to the group—S-substituted heteroaryl.

The term “thioheterocyclic” as used herein refers to the group—S-heterocyclic.

The term “substituted thioheterocyclic as used herein refers to thegroup —S-substituted heterocyclic.

The term “amino acid sidechain” refers to the Z₇ substituent of α-aminoacids of the formula Z₆NHCH(Z₇)COOH where Z₇ is selected from the groupconsisting of hydrogen, alkyl, substituted alkyl and aryl and Z₆ ishydrogen or together with Z₇ and the nitrogen and carbon atoms boundthereto respectively form a heterocyclic ring. In one embodiment, theα-amino acid sidechain is the sidechain of one of the twenty naturallyoccurring L amino acids.

Sugars described herein may either be in D or L configuration.

Compounds of Formula I

Compounds of the invention include compounds of formula I:

wherein;

B represents a 5, 6, 7 or 8 membered carbocyclic or heterocyclic ringcomprising one or more double bonds, wherein B is optionally substitutedwith one or more oxo, thioxo, NR_(c)R_(d), F, Cl, Br, I, OR_(z), SR_(z),alkyl, C≡N, C≡C—R, N₃ or SO₂R′;

wherein:

R is H, alkyl or aryl;

R′ is OH, NH₂ or alkyl;

R¹ is H, NR_(a)R_(b), Cl, F, OR_(a), SR_(a), NHCOR_(a), NHSO₂R_(a),NHCONHR_(a), CN, alkyl, aryl, ONR_(a)R_(b), or NR_(a)C(O)OR_(b);

R² is a nucleoside sugar group;

W³ is absent, alkyl, or H;

R_(a) and R_(b) are independently selected from the group consisting ofH, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl,substituted alkynyl, cycloalkyl, heterocyclic, aryl, substituted aryl,acyl, substituted acyl, SO₂-alkyl, amino, substituted amino, and NO; orR_(a) and R_(b) together with the nitrogen to which they are attachedform a pyrrolidino, piperidino, piperazino, azetidino, morpholino, orthiomorpholino ring;

R_(c) and R_(d) are independently selected from the group consisting ofH, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl,substituted alkynyl, cycloalkyl, acyl, substituted acyl and SO₂-alkyl;or R_(c) and R_(d) together with the nitrogen to which they are attachedform a pyrrolidino, piperidino, piperazino, azetidino, morpholino, orthiomorpholino ring; and

each R_(z) is independently selected from the group consisting of H,alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl,substituted alkynyl, cycloalkyl, acyl and substituted acyl;

or a pharmaceutically acceptable salt or prodrug thereof.

In one embodiment of the invention the compound of formula I is acompound of formula II:

wherein;

B represents a 5, 6, 7 or 8 membered ring comprising one or moreheteratoms and one or more double bonds, wherein B is optionallysubstituted with one or more oxo, thioxo, NR_(c)R_(d), F, Cl, Br, I,OR_(z), SR_(z), alkyl, C≡N, C≡C—R, N₃ or SO₂R′;

wherein:

R is H, alkyl or aryl;

R′ is OH, NH₂ or alkyl;

R¹ is H, NR_(a)R_(b), Cl, F, OR_(a), SR_(a), NHCOR_(a), NHSO₂R_(a),NHCONHR_(a), CN, alkyl, aryl, ONR_(a)R_(b), or NR_(a)C(O)OR_(b);

R² is a nucleoside sugar group;

W³ is absent, alkyl, or H;

R_(a) and R_(b) are independently selected from the group consisting ofH, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl,substituted alkynyl, cycloalkyl, heterocyclic, aryl, substituted aryl,acyl, substituted acyl, SO₂-alkyl, amino, substituted amino, and NO; orR_(a) and R_(b) together with the nitrogen to which they are attachedform a pyrrolidino, piperidino, piperazino, azetidino, morpholino, orthiomorpholino ring;

R_(c) and R_(d) are independently selected from the group consisting ofH, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl,substituted alkynyl, cycloalkyl, acyl, substituted acyl and SO₂-alkyl;or R_(c) and R_(d) together with the nitrogen to which they are attachedform a pyrrolidino, piperidino, piperazino, azetidino, morpholino, orthiomorpholino ring; and

each R_(z) is independently selected from the group consisting of H,alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl,substituted alkynyl, cycloalkyl, acyl and substituted acyl;

or a pharmaceutically acceptable salt or prodrug thereof.

In one embodiment of the invention the compound of formula I is acompound of formula II wherein W³ is absent or H.

In one embodiment of the invention the compound of formula I is acompound of formula III:

wherein:

each b, c and d is independently selected from a single and double bondprovided that when b is a double bond, c is single bond, when c is adouble bond, b and d are single bonds and when d is a double bond c is asingle bond; or d is absent when W² is absent; and W² and d are notabsent, when bNW³ is absent;

W is C═R_(e), CH₂, CR_(g) or O, provided that when W is C═R_(e), CH₂ orO, b and c are single bonds, or c is a single bond and bNW³ is absent;and provided when W is CR_(g), one of b or c is a double bond, or bNW³is absent and c is a double bond;

R_(e) is O or S;

R_(g) is H, NR_(c)R_(d), OR_(z) or SR_(z);

W¹ is C═R_(h), N, NR_(n), CR_(j) or O provided that when W¹ is C═R_(h),CR_(i)R_(i), NR_(n) or O, c and d are single bonds or c is a single bondand W²d is absent; and provided when W¹ is CR_(j) or N one of c or d isa double bond or W2d is absent and c is a double bond;

R_(h) is O or S;

R_(i) and R_(i′) are H, CH₃, NH₂ or Br;

R_(j) is CH₃, NH₂, or H;

W² is C═R_(k), (CR_(l)R_(l′))_(p′), CR_(m), O, NR_(S), absent or Nprovided that when W² is C═R_(k), CR_(l)R_(l′), O, or NR_(s) d is asingle bond; when W² is N or CR_(m) d is a double bond; and providedwhen W² is absent, d is absent;

R_(k) is O or S;

R_(l) and R_(l′) are H, CH₃, OCH₃, NH₂ or SCH₃;

p′ is 1 or 2;

R_(m) is H, NR_(c)R_(d), F, Cl, Br, I, OR_(z), SR_(z), alkyl, C≡N,C≡C—R, N₃ or SO₂R′;

R_(n) is H, alkyl, or NR_(q)R_(r) wherein each R_(q) and R_(r) is H oralkyl;

R_(s) is H, CH₃, or NH₂; and

W³ is absent, H or alkyl; provided that when W³ is absent b is a doublebond;

or a pharmaceutically acceptable salt or prodrug thereof.

In one embodiment of the invention the compound of formula I is acompound of formula IV:

wherein:

each b, c and d is independently selected from a single or double bondprovided that when b is a double bond, c is single bond, when c is adouble bond, b and d are single bonds and when d is a double bond c is asingle bond; or d is absent when W² is absent;

W is C═R_(e), CR_(f)R_(f), CR_(g) or O, provided that when W is C═R_(e),CR_(f)R_(f) or O, b and c are single bonds and when W is CR_(g), one ofb or c is a double bond;

R_(e) is O or S;

R_(f) is H;

R_(g) is H, NR_(c)R_(d), OR_(z) or SR_(z);

W¹ is C═R_(h), CR_(i)R_(i′), NH, CR_(j) or O provided that when W¹ isC═R_(h), CR_(i)R_(i), or O, c and d are single bonds; when W¹ is CR_(j),one of c or d is a double bond; and when W¹ is NH, W is not O and W² isnot O, NH, or N;

R_(h) is O or S;

R_(i) and R_(i′) are H, CH₃ or Br;

R_(j) is CH₃ or H;

W² is C═R_(k), (CR_(l)R_(l′))_(p′), CR_(m), O, NH, absent, or N providedthat when W² is C═R_(k), CR_(l)R_(l′), CR_(m), O, or NH d is a singlebond; when W² is N or CR_(m) d is a double bond; or when W² is absent, dis absent;

R_(k) is O or S;

R_(l) and R_(l′), are H, CH₃, OCH₃ or SCH₃;

p′ is 1 or 2;

R_(m) is H, NR_(c)R_(d), F, Cl, Br, I, OR_(z), SR_(z), alkyl, C≡N,C≡C—R, N₃ or SO₂R′; and W³ is absent, H or alkyl; provided that when W³is absent b is a double bond;

or a pharmaceutically acceptable salt or prodrug thereof.

In one embodiment of the invention the compound of formula I is acompound of formula IV wherein: each b, c and d is independentlyselected from a single or double bond provided that when b is a doublebond, c is single bond, when c is a double bond, b and d are singlebonds and when d is a double bond c is a single bond;

W is C═R_(e), CR_(f)R_(f), CR_(g) or O, provided that when W is C═R_(e),CR_(f)R_(f) or O, b and c are single bonds and when W is CR_(g), one ofb or c is a double bond;

R_(e) is O or S;

R_(f) is H;

R_(g) is H, NR_(c)R_(d), OR_(z) or SR_(z);

W¹ is C═R_(h), CR_(i)R_(i′), CR_(j) or O provided that when W¹ isC═R_(h), CR_(i)R_(i), or O, c and d are single bonds and when W¹ isCR_(j), one of c or d is a double bond;

R_(h) is O or S;

R, and R¹, are H, CH₃ or Br;

R., is CH₃ or H;

W² is C═R_(k), (CR_(l)R_(l′))_(p′), CR_(m), O, NH or N provided thatwhen W² is C═R_(k), CR_(l)R_(l′), CR_(m), O, or NH d is a single bondand when W² is N or CR_(m) d is a double bond;

R_(k) is O or S;

R_(l) and R_(l′) are H, CH₃, OCH₃ or SCH₃;

p′ is 1 or 2;

R_(m) is H, NR_(c)R_(d), F, Cl, Br, I, OR_(z), SR_(z), alkyl, C≡N,C≡C—R, N₃ or SO₂R′; and

W³ is absent or H, provided that when W³ is absent b is a double bond;

or a pharmaceutically acceptable salt or prodrug thereof.

In one embodiment of the invention the compound of formula I is acompound of formula V:

wherein:

each of b and c is independently selected from a single or double bondprovided that when b is a double bond, c is single bond and when c is adouble bond b is a single bond;

W is C═R_(e), CR_(f)R_(f), CR_(g) or O, provided that when W is C═R_(e),CR_(f)R_(f) or O, b and c are single bonds and when W is CR_(g), one ofb or c is a double bond;

R_(e) is O or S;

R_(f) is H;

R_(g) is H, NR_(c)R_(d), OR_(z) or SR_(z);

W¹ is C═R_(h), CR_(i)R_(i′), NH, CR_(j) or O provided that when W¹ isC═R_(h), CR_(i)R_(i), or O, c is a single bond; when W¹ is CR_(j), c isa double bond; and when W¹ is NH, W is not O;

R_(h) is O or S;

R_(i) and R_(i′) are each independently H, CH₃ or Br;

R_(j) is CH₃ or H; and

W³ is absent, H, or alkyl, provided that when W³ is absent b is a doublebond;

or a pharmaceutically acceptable salt or prodrug thereof.

In one embodiment of the invention the compound of formula I is acompound of formula V wherein W³ is absent, H, or methyl.

In one embodiment of the invention the compound of formula I is acompound of formula V wherein W³ is methyl.

In another embodiment of the invention provides compounds of formula Ithat are compounds of formula 1-9:

wherein:

X¹ is O, S, or two hydrogens;

X² is O, S, or two hydrogens;

X³ is O or S;

X⁴ is O, S, or two hydrogens;

X⁵ is O, S, or two hydrogens;

X⁸ is NH₂, OCH₃ or SCH₃;

Y¹ is H, OH, NH₂, NHCH₃, N(CH₃)₂, F, Cl, Br, I, OCH₃, Oalkyl, alkylSCH₃, CH₃, C≡N, C≡C—R, N₃ or SO₂R′;

Y² is H, CH₃, OCH₃ or SCH₃;

Y³ is O or S;

Y⁴ is O, S, or two hydrogens;

Z¹ is H or CH₃;

Z² is H, CH₃ or Br; and

t is 1 or 2;

or a pharmaceutically acceptable salt or prodrug thereof.

In another embodiment the invention provides a compound of Formula I asdescribed above, wherein R¹ is H or NR_(a)R_(b); or a pharmaceuticallyacceptable salt or prodrug thereof.

In another embodiment the invention provides a compound of Formula I asdescribed above, wherein R² is a nucleoside sugar group of Group A, B,C, D, E, or F described hereinbelow; or a pharmaceutically acceptablesalt or prodrug thereof.

In another embodiment the invention provides a compound of Formula I asdescribed above, wherein R² is ribose, 2-methylribose, 2-deoxyribose;2-deoxy-2-fluororibose; arabinose;

-   2-deoxy-2-fluoroarabinose; 2,3-dideoxyribose;    2,3-dideoxy-2-fluoroarabinose; 2,3-dideoxy-3-fluororibose;    2,3-dideoxy-2,3-didehydroribose; 2,3-dideoxy-3-azidoribose;    2,3-dideoxy-3-thiaribose; or 2,3-dideoxy-3-oxaribose; or a    pharmaceutically acceptable salt or prodrug thereof.

In another embodiment the invention provides a compound of Formula I asdescribed above, wherein R² is thioribose, 2-deoxythioribose;2-deoxy-2-fluorothioribose; thioarabinose;2-deoxy-2-fluorothioarabinose; 2,3-dideoxythioribose;2,3-dideoxy-2-fluorothioarabinose; 2,3-dideoxy-3-fluorothioribose;2,3-dideoxy-2,3-didehydrothioribose; or 2,3-dideoxy-3-azidothioribose;or a pharmaceutically acceptable salt or prodrug thereof.

In another embodiment the invention provides a compound of Formula I asdescribed above, wherein R² is 4-hydroxymethylcyclopent-2-ene;2,3-dihydroxy-4-hydroxymethylcyclopent-4-ene;3-hydroxy-4-hydroxymethylcyclopentane;2-hydroxy-4-hydroxymethylcyclopentene;2-fluoro-3-hydroxy-4-hydroxymethylcyclopentane;2,3-dihydroxy-4-hydroxymethyl-5-methylenecyclopentane;4-hydroxymethylcyclopentane, 2,3-dihydroxy-4-hydroxymethylcyclopentane;or 2,3-dihydroxymethylcyclobutane; or a pharmaceutically acceptable saltor prodrug thereof.

In another embodiment the invention provides a compound of Formula I asdescribed above, wherein R² is 4-hydroxymethylpyrrolidine;2,3-dihydroxy-4-hydroxymethylpyrrolidine;2/3-hydroxy-4-hydroxymethylpyrrolidine;2-fluoro-3-hydroxy-4-hydroxymethylpyrrolidine; or3-fluoro-2-hydroxy-4-hydroxymethyl-pyrrolidine; or a pharmaceuticallyacceptable salt or prodrug thereof.

In another embodiment the invention provides a compound of Formula I asdescribed above, wherein R_(a), R_(b), R_(c), and R_(d) areindependently selected from the group consisting of H, alkyl, andsubstituted alkyl; or R_(a) and R_(b) together with the nitrogen towhich they are attached form a pyrrolidino, piperidino, piperazino,azetidino, morpholino, or thiomorpholino ring; or R_(b) and R_(c)together with the nitrogen to which they are attached form apyrrolidino, piperidino, piperazino, azetidino, morpholino, orthiomorpholino ring.

In another embodiment the invention provides a compound selected from,

or a pharmaceutically acceptable salt or prodrug thereof.

In one embodiment the invention provides a compound of formula Iselected from:

or a pharmaceutically acceptable salt or prodrug thereof.

In another embodiment the invention the compound of formula (I) is not acompound of the following formula (X):

or a pharmaceutically acceptable salt or prodrug thereof; wherein X is Hor alkyl.

In another embodiment the invention the compound of formula (I) is not acompound of the following formula:

or a pharmaceutically acceptable salt or prodrug thereof; wherein X is Hor methyl; and R′⁷ is H or methyl.

In another embodiment the invention B is not a 6 membered ringcomprising two nitrogens and one double bond, wherein B is substitutedwith NR_(c)R_(d).

In another embodiment the invention B represents a 5, 7, or 8 memberedring comprising one or more heteratoms and one or more double bonds,wherein B is optionally substituted with one or more oxo, thioxo,NR_(c)R_(d), F, Cl, Br, I, OR_(z), SR_(z), alkyl, C≡N, C≡C—R, N₃ orSO₂R′.

In another embodiment the invention the compound of formula (I) is:

or a pharmaceutically acceptable salt or prodrug thereof.

In another embodiment the invention the compound of formula (I) is:

or a pharmaceutically acceptable salt or prodrug thereof.In another embodiment the invention the compound of formula (I) is:

or a pharmaceutically acceptable salt or prodrug thereof.

In another embodiment the invention the compound of formula (I) is:

or a pharmaceutically acceptable salt or prodrug thereof.

In another embodiment the invention B represents a 5 membered ringcomprising one or more heteratoms (e.g. 1, 2, or 3) and one or moredouble bonds (e.g. 1, 2, or 3), wherein B is optionally substituted withone or more (e.g. 1, 2, or 3) oxo, thioxo, NR_(c)R_(d), F, Cl, Br, I,OR_(z), SR_(z), alkyl, C≡N, C≡C—R, N₃ or SO₂R′.

In another embodiment the invention B represents a 6 membered ringcomprising one or more heteratoms (e.g. 1, 2, or 3) and one or moredouble bonds (e.g. 1, 2, or 3), wherein B is optionally substituted withone or more (e.g. 1, 2, or 3) oxo, thioxo, NR_(c)R_(d), F, Cl, Br, I,OR_(z), SR_(z), alkyl, C≡N, C≡C—R, N₃ or SO₂R′.

In another embodiment the invention B represents a 7 membered ringcomprising one or more heteratoms (e.g. 1, 2, or 3) and one or moredouble bonds (e.g. 1, 2, or 3), wherein B is optionally substituted withone or more (e.g. 1, 2, or 3) oxo, thioxo, NR_(C)R_(d), F, Cl, Br, I,OR_(z), SR_(z), alkyl, C≡N, C≡C—R, N₃ or SO₂R′.

In another embodiment the invention B represents an 8 membered ringcomprising one or more heteratoms (e.g. 1, 2, or 3) and one or moredouble bonds (e.g. 1, 2, or 3), wherein B is optionally substituted withone or more (e.g. 1, 2, or 3) oxo, thioxo, NR_(c)R_(d), F, Cl, Br, I,OR_(z), SR_(z), alkyl, C≡N, C≡C—R, N₃ or SO₂R′.

Prodrugs

The term “prodrug” as used herein refers to a compound that can bemetabolized in vivo to provide a compound of Formula I. Thus prodrugsinclude compounds that can be prepared by modifying one or morefunctional groups in a compound of Formula I to provide a correspondingcompound that can be metabolized in vivo to provide a compound ofFormula I. Such modifications are known in the art. For example, one ormore hydroxy groups or amine groups in a compound of Formula I can beacylated with alkyl-C(═O)-groups or with residues from amino acids toprovide a prodrug. Alternatively, one or more pendent hydroxyl groupsfrom a mono-, di-, or tri-phosphate functionality in a compound ofFormula I can be converted to an alkoxy, substituted alkoxy, aryloxy, orsubstituted aryloxy group.

In one embodiment, the term prodrug includes a compound wherein one ormore hydroxy groups on a nucleoside sugar group (e.g. a 2′, 3′, or 5′hydroxy group) have been converted to a group that can be metabolized invivo to provide a compound of Formula I. For example, the inventionprovides a compound wherein one or more hydroxy groups on a nucleosidesugar group (e.g. a 2′, 3′, or 5′ hydroxy group) have been converted toan acyloxy, acylamino or R—O group, wherein R is a carboxy-linled aminoacid.

In one embodiment, the term prodrug includes a compound wherein one ormore pendent hydroxyl groups from a mono-, di-, or tri-phosphatefunctionality in a compound of Formula I is converted to a groupR_(y)—O—; wherein each R_(y) is independently a 1-20 carbon branched orunbranched, saturated or unsaturated chain, wherein one or more (e.g. 1,2, 3, or 4) of the carbon atoms is optionally replaced with —O— or —S—and wherein one or more of the carbon atoms is optionally substitutedwith oxo (═O) or thioxo (═S) (See Lefebvre et al., J. Med. Chem. 1995,38, 3941-50).

In another embodiment, the term prodrug includes a compound wherein oneor more pendent hydroxyl groups from a mono-, di-, or tri-phosphatefunctionality in a compound of Formula I is converted to a groupR_(z)N—; wherein each R_(z) is a residue of an amino acid. Thus, in themethods of treatment of the present invention, the term “administering”includes administration of a compound of Formula I, as well asadministration of a prodrug which converts to a compound of Formula I ora salt thereof in vivo. Conventional procedures for the selection andpreparation of prodrug derivatives are described, for example, in“Design of Prodrugs”, ed. H. Bundgaard, Elsevier, 1985; and inInternational Patent Application Publication Number WO 2005/084192. Avariety of prodrugs are also described in International PatentApplication Number PCT US2004/013063, which was published asInternational Publication Number WO 2004/096286.

In another embodiment the prodrug comprises one of more groups offormula:

wherein:

R₁₅ is H, alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl,substituted cycloalkyl, heteroaryl, substituted heteroaryl,heterocyclic, substituted heterocyclic, and an amino acid;

R₁₆ is H, optionally substituted monocyclic aryl, or optionallysubstituted monocyclic heteroaryl; and R₁₇ is H, halogen, CN, —CO—R₂₀,—CON(R₂₁)₂, —CO₂R₂₀, —SO₂R₂₀, —SO₂N(R₂₁)₂, —OR₂₁, —SR₂₁, —R₂₁, —N(R₂₁)₂,—O—COR₂₀, —O—CO₂R₂₀, —SCOR₂₀, —S—CO₂R₂₀, —NHCOR₂₁, —NHCO₂R₂₁,—(CH₂)_(p)—OR₂₂, or —(CH₂)_(p)—SR₂₂; or R₁₆ and R₁₇ are connected via anadditional 3-5 atoms to form a cyclic group, optionally containing oneheteroatom, that is fused to an aryl group at the beta and gammaposition to the O attached to the phosphorus; or R₁₇ and R₁₈ areconnected as described below;

R₁₈ and R₁₉ are each independently H, alkyl, aryl, heterocycloalkyl,aralkyl, optionally substituted monocyclic aryl or optionallysubstituted monocyclic heteroaryl; or R₁₈ and R₁₉ are connected via anadditional 2-5 atoms to form a cyclic group, optionally containing 0-2heteroatoms; or R₁₇ and R₁₈ are connected via an additional 3-5 atoms toform a cyclic group, optionally containing one heteroatom and R₁₉ is H,alkyl, aryl, heterocycloalkyl, aralkyl, optionally substitutedmonocyclic aryl or optionally substituted monocyclic heteroaryl; and

R₂₀ is alkyl, aryl, heterocycloalkyl, or arylalkyl;

R₂₁ is H, alkyl, aryl, heterocycloalkyl, or arylalkyl;

R₂₂ is H or lower acyl;

n is an integer from 2-5;

m is an integer from 10-20; and p is an integer from 2-3.

Prodrug forms of a compound bearing various nitrogen functions (amino,hydroxyamino, amide, etc.) may include the following types ofderivatives where each R_(p) group individually may be hydrogen,substituted or unsubstituted alkyl, aryl, alkenyl, alkynyl, heterocycle,alkylaryl, aralkyl, aralkenyl, aralkynyl, cycloalkyl or cycloalkenylgroups as defined earlier.

-   -   (a) Carboxamides, represented as —NHC(O)R_(p)    -   (b) Carbamates, represented as —NHC(O)OR_(p)    -   (c) (Acyloxy)alkyl Carbamates, represented as NHC(O)OROC(O)R_(p)    -   (d) Enamines, represented as —NHCR(═CHCO₂R_(p)) or        —NHCR(═CHCONR_(p)R_(p))    -   (e) Schiff Bases, represented as —N═CR_(p)R_(p)    -   (f) Mannich Bases (from carboximide compounds), represented as        RCONHCH₂NR_(p)R_(p)        Preparations of such prodrug derivatives are discussed in        various literature sources (examples are: Alexander et al., J.        Med. Chem. 1988, 31, 318; Aligas-Martin et al., PCT        WO0041531, p. 30).

Prodrug forms of carboxyl-bearing compounds include esters (—CO₂R_(m))where the R_(m) group corresponds to any alcohol whose release in thebody through enzymatic or hydrolytic processes would be atpharmaceutically acceptable levels. Another prodrug derived from acarboxylic acid form of the disclosure may be a quaternary salt type ofstructure described by Bodor et al., J. Med. Chem. 1980, 23, 469.

Nucleoside Sugar Groups

The term “nucleoside sugar group” as used herein includes cyclic andacyclic groups that can be included as the sugar portion of a nucleosideanalog of Formula I. Many examples of such groups are known in the fieldof nucleoside chemistry (See for example Antiviral Drugs by John S.Driscoll (2002) published by Ashgate Publishing Ltd.).

The term nucleoside sugar group includes substituted and unsubstitutedtetrahydrofuranyl and dihydrofuranyl compounds including those set forthin group (A) below, substituted and unsubstituted tetrahydrothiophenyland dihydrothiophenyl compounds including those set forth in group (B)below, substituted and unsubstituted alkyl compounds including those setforth in group (C) below, substituted and unsubstituted cycloalkyl andcycloalkenyl compounds including those set forth in group (D) below,substituted and unsubstituted dihydropyrrolidinyl andtetrahydropyrrolidinyl compounds including those set forth in group (E)below, and substituted and unsubstituted dioxolane, substituted andunsubstituted thioxolane, and substituted and unsubstituted dithiolanecompounds including those set forth in group (F) below.

Group A

Examples of substituted tetrahydro and dihydrofuranyl compounds includethose compounds represented by the general structures:

Specific examples include, but are not limited to, the followingcompounds:

Group B

Examples of substituted tetrahydrothiophenyl and dihydrothiophenylcompounds include those compounds represented by the general structures:

Specific examples include, but are not limited to, the followingcompounds:

Group C

Examples of substituted alkyl compounds include those compoundsrepresented by:

Specific examples include, but are not limited to, the followingcompounds:

Group D

Examples of substituted cycloalkyl and cycloalkenyl compounds includethose compounds represented by the general structures:

Specific examples include, but are not limited to, the followingcompounds:

Group E

Examples of substituted dihydropyrrolidinyl and tetrahydropyrrolidinylcompounds include those compounds represented by the general structures:

Specific examples include, but are not limited to, the followingcompounds:

Group F

Examples of substituted dioxolane, substituted thioxolane andsubstituted dithiolane compounds include those compounds represented bythe general structures:

Specific examples include, but are not limited to, the followingcompounds:

For the structures in Groups A-F, the following definitions apply:

R₇ is H, OR₁₄, N₃, NH₂, or F; and R′₇ is H, F, OH, O-alkyl, alkyl,substituted alkyl, alkenyl, substituted alkenyl, alkynyl, or substitutedalkynyl; or R₇ and R′₇ together may be ═CH₂, ═CHF; wherein both R₇ andR′₇ are not OH; and when one of R₇ and R′₇ is NH₂, the other is not OH;and when one of R₇ and R′₇ is N₃, the other is not OH;

R₈ is H, OR₁₄, N₃, NH₂, or F; and R′₈ is H, F, OH, O alkyl, alkyl,substituted alkyl, alkenyl, substituted alkenyl, alkynyl, or substitutedalkynyl; or R₈ and R′₈ together may be ═CH₂, ═CHF; wherein both R₈ andR′₈ are not OH; and when one of R₈ and R′₈ is NH₂, the other is not OH;and when one of R₈ and R′₈ is N₃, the other is not OH;

or R₇ and R₈ together can form

wherein: R₁₀₀ is C₁₋₁₂ alkyl C₃₋₈ cycloalkyl, aryl or heteroaryl;wherein any C₁₋₁₂ alkyl and C₃₋₈ cycloalkyl of R₁₀₀ is unsubstituted oris substituted with 1-3 substituents selected from halogen, hydroxy,carboxy, and C₁₋₄ alkoxy; and wherein any aryl or heteroaryl of R₁₀₀ isunsubstituted or is substituted with 1-5 substituents independentlyselected from R₁₀₁;

each R₁₀₁ is independently halo, C₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₄alkylthio, C_(i) alkylsulfoyl, cyano, nitro, amino, phenyl, carboxy,trifluoromethyl, trifluoromethoxy, C₁₋₄ alkylamino, di(C₁₋₄ alkyl)amino,C₁₋₄ alkanoyl, C₁₋₄ alkanoyloxy, or C₁₋₄ alkyloxycarbonyl;

R₉ is H, CH₃, C₂H₅, or N₃;

R′₉ is CH₂OR₁₄, CH₂F, CH₂SH, CHFOH, CF₂OH, CH₂-diphosphate,CH₂-triphosphate,

R₁₀ and R₁₁ are each independently H, alkyl, aryl, substituted aryl,acyloxyalkyl, or (CH₂)_(n)—O—(CH₂)_(m)CH₃;

R₁₂ is an N-linked amino acid residue (e.g.—NH—CH(CH₃)CO₂alkyl or—NH—CH(isopropyl)-CO₂alkyl); and

R₁₄ is H;

n is 2-5; and

m is 10-20.

In one specific embodiment of the invention for the structures in GroupsA-F:

R₇ is H, OR₁₄, N₃, NH₂, or F; and R′₇ is H, F, OH, O-alkyl, alkyl,substituted alkyl, alkenyl, substituted alkenyl, alkynyl, or substitutedalkynyl; or R₇ and R′₇ together may be ═CH₂, ═CHF; wherein both R₇ andR′₇ are not OH; and when one of R₇ and R′₇ is NH₂, the other is not OH;and when one of R₇ and R′₇ is N₃, the other is not OH; R₇″ is alkyl orsubstituted alkyl.

R₈ is H, OR₁₄, N₃, NH₂, or F; and R′₈ is H, F, OH, O alkyl, alkyl,substituted alkyl, alkenyl, substituted alkenyl, alkynyl, or substitutedalkynyl; or R₈ and R′₈ together may be ═CH₂, ═CHF; wherein both R₈ andR′₈ are not OH; and when one of R₈ and R′₈ is NH₂, the other is not OH;and when one of R₈ and R′₈ is N₃, the other is not OH;

R₉ is H, CH₃, C₂H₅, or N₃;

R′₉ is CH₂OR₁₄, CH₂F, CH₂SH, CHFOH, CF₂OH,

R₁₀ and R₁₁ are each independently H, alkyl, aryl, substituted aryl,acyloxyalkyl, or (CH₂)_(n)—O—(CH₂)_(In)CH₃;

R₁₂ is an N-linked amino acid residue (e.g.—NH—CH(CH₃)CO₂alkyl or—NH—CH(isopropyl)-CO₂alkyl);

R₁₃ is H, CH₃, C₂H₅, CH₂F, CH₂OH, CH₂CH₂F, CH₂CH₂OH, CH₂N₃, CH₂CH₂N₃,

CH₂NH₂, or CH₂CH₂NH₂;

R₁₄ is H;

n is 2-5; and

m is 10-20.

In one embodiment, for a compound of Formula I, R₁₄ is replaced to forma pharmaceutically acceptable prodrug, for example, a prodrug selectedfrom the group consisting of: acyl, oxyacyl, phosphonate, phosphate,phosphate esters, phosphonamidate, phosphorodiamidate, phosphoramidatemono ester, cyclic phosphoramidate, cyclic phosphorodiamidate,phosphoramidate diester, C(O)CHR₁₅NH₂,

wherein:

R₁₅ is H, alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl,substituted cycloalkyl, heteroaryl, substituted heteroaryl,heterocyclic, substituted heterocyclic, or an amino acid;

R₁₆ is H, optionally substituted monocyclic aryl, or optionallysubstituted monocyclic heteroaryl; and R₁₇ is H, halogen, CN, —CO—R₂₀,—CON(R₂₁)₂, —CO₂R₂₀, —SO₂R₂₀, —SO₂N(R₂₁)₂, —OR₂₁, —SR₂₁, —R₂₁, —N(R₂₁)₂,—O—COR₂₀, —O—CO₂R₂₀, —SCOR₂₀, —S—CO₂R₂₀, —NHCOR₂₁, —NHCO₂R₂₁,—(CH₂)_(p)—OR₂₂, or —(CH₂)_(p)—SR₂₂; or R₁₆ and R₁₇ are connected via anadditional 3-5 atoms to form a cyclic group, optionally containing oneheteroatom, that is fused to an aryl group at the beta and gammaposition to the O attached to the phosphorus; or R₁₇ and R₁₈ areconnected as described below;

R₁₈ and R₁₉ are each independently H, alkyl, aryl, heterocycloalkyl,aralkyl, optionally substituted monocyclic aryl or optionallysubstituted monocyclic heteroaryl; or R₁₈ and R₁₉ are connected via anadditional 2-5 atoms to form a cyclic group, optionally containing 0-2heteroatoms; or R₁₇ and R₁₈ are connected via an additional 3-5 atoms toform a cyclic group, optionally containing one heteroatom and R₁₉ is H,alkyl, aryl, heterocycloalkyl, aralkyl, optionally substitutedmonocyclic aryl or optionally substituted monocyclic heteroaryl; and

R₂₀ is alkyl, aryl, heterocycloalkyl, or arylalkyl;

R₂₁ is H, alkyl, aryl, heterocycloalkyl, or arylalkyl;

R₂₂ is H or lower acyl; and

p is an integer from 2-3.

Synthetic Processes

Processes for preparing compounds of Formula I, or a pharmaceuticallyacceptable salts or prodrugs thereof, as well as processes for preparingintermediate compounds that can be used to prepare compounds of FormulaI or pharmaceutically acceptable salts or prodrugs thereof are providedas further embodiments of the invention. For example in one embodimentthe invention provides a method for preparing a pharmaceuticallyacceptable salt of compound of Formula I comprising converting acorresponding compound of Formula I to the salt.

In another embodiment the invention provides a method for preparing aprodrug of a compound of Formula I comprising converting a correspondingcompound of Formula I to the prodrug.

In another embodiment the invention provides a method for preparing acompound of Formula I comprising deprotecting a corresponding compoundof Formula I that comprises one or more protecting groups to provide thecompound of Formula I.

Synthetic Intermediates

The invention also provides synthetic intermediates that are useful forpreparing compounds of Formula I or a salt or prodrug thereof. Forexample, the invention provides novel synthetic intermediates such asthose described in the Examples herein.

Isomers and Physical Forms

It will be appreciated by those skilled in the art that compounds of theinvention having a chiral center may exist in and be isolated inoptically active and racemic forms. Some compounds may exhibitpolymorphism. It is to be understood that the present inventionencompasses any racemic, optically-active, polymorphic, tautomeric, orstereoisomeric form, or mixtures thereof, of a compound of the invention(e.g. a compound of Formula I, which possess the useful propertiesdescribed herein, it being well known in the art how to prepareoptically active forms (for example, by resolution of the racemic formby recrystallization techniques, by synthesis from optically-activestarting materials, by chiral synthesis, or by chromatographicseparation using a chiral stationary phase) and how to determineanti-viral or anti-cancer activity using the standard tests describedherein, or using other similar tests which are well known in the art.Although the invention includes all isomeric forms of the compoundsdescribed herein, one embodiment of the invention provides compoundshaving the absolute stereochemistry depicted in the Exampleshereinbelow.

Pharmaceutical Compositions, Modes of Administration and Methods ofTreatment

The present disclosure provides compounds of the general Formula I asdetailed above which are inhibitors of DNA and/or RNA viral polymerasesand anticancer agents. Various forms of DNA and RNA viral polymerasesare inhibited by the compounds disclosed, such as but not limited toviral RdRps. The compounds of the present disclosure therefore haveutility in treating and/or preventing viral infections in a host and intreatment and/or preventing a variety of disease states and/orconditions caused by or related to such viral infections. In oneembodiment, the compounds are useful in the above mentioned treatingand/or preventing by inhibiting a viral RNA and DNA polymerases. Suchviral agents include, but are not limited to, hepatitis B, hepatitis C,human immunodeficiency virus, Polio, Coxsackie A and B, Rhino, Echo,small pox, Ebola, and West Nile virus. In a particular embodiment, thecausative agent of the viral infection is a flavivirus.

The present disclosure provides for a compound of the general Formula Iand a pharmaceutical composition comprising a pharmaceutically effectiveamount of at least one compound of general Formula I as describedherein. Such compounds and/or pharmaceutical compositions may be used inthe manufacture of a medicament for treating and/or preventing a diseaseor condition in which it is desirable to inhibit a viral RNA and DNApolymerases. Such pharmaceutical compositions may also comprise apharmaceutically acceptable carrier and other ingredients known in theart, or may comprise solely a compound of the general Formula I.

The pharmaceutically acceptable carriers described herein, including,but not limited to, vehicles, adjuvants, excipients, or diluents, arewell-known to those who are skilled in the art. Typically, thepharmaceutically acceptable carrier is chemically inert to the activecompounds and has no detrimental side effects or toxicity under theconditions of use. The pharmaceutically acceptable carriers can includepolymers and polymer matrices.

The compounds described in the instant disclosure can be administered byany conventional method available for use in conjunction withpharmaceuticals, either as individual therapeutic agents or incombination with additional therapeutic agents.

The compounds described are administered in a pharmaceutically effectiveamount. The pharmaceutically effective amount of the compound and thedosage of the pharmaceutical composition administered will, of course,vary depending upon known factors, such as the pharmacodynamiccharacteristics of the particular agent and its mode and route ofadministration; the age, health and weight of the recipient; theseverity and stage of the disease state or condition; the kind ofconcurrent treatment; the frequency of treatment; and the effectdesired.

A daily dosage of active ingredient can be expected to be about 0.001 to1000 milligrams (mg) per kilogram (kg) of body weight per day. In oneembodiment, the total amount is between about 0.1 mg/kg and about 100mg/kg of body weight per day; in an alternate embodiment between about1.1 mg/kg and about 50 mg/kg of body weight per day; in yet anotheralternate embodiment between 0.1 mg/kg and about 30 mg/kg of body weightper day. The above described amounts may be administered as a series ofsmaller doses over a period of time if desired. The pharmaceuticallyeffective amount can be calculated based on the weight of the parentcompound to be delivered. If the salt or prodrug exhibits activity initself, the pharmaceutically effective amount can be estimated as aboveusing the weight of the salt or prodrug, or by other means known tothose skilled in the art. The dosage of active ingredient may be givenother than daily if desired.

The total amount of the compound administered will also be determined bythe route, timing and frequency of administration as well as theexistence, nature, and extent of any adverse side effects that mightaccompany the administration of the compound and the desiredphysiological effect. It will be appreciated by one skilled in the artthat various conditions or disease states, in particular chronicconditions or disease states, may require prolonged treatment involvingmultiple administrations.

Dosage forms of the pharmaceutical compositions described herein (formsof the pharmaceutical compositions suitable for administration) containfrom about 0.1 mg to about 3000 mg of active ingredient (i.e. thecompounds disclosed) per unit. In these pharmaceutical compositions, theactive ingredient will ordinarily be present in an amount of about0.5-95% weight based on the total weight of the composition. Multipledosage forms may be administered as part of a single treatment. Theactive ingredient may be administered to achieve peak plasmaconcentrations of the active ingredient of from about 0.2 to 70 μM, orfrom about 1.0 to 10 μM.

The active ingredient can be administered orally in solid dosage forms,such as capsules, tablets, and powders, or in liquid dosage forms, suchas elixirs, syrups and suspensions. It can also be administeredparenterally, in sterile liquid dosage forms. The active ingredient canalso be administered intranasally (nose drops) or by inhalation via thepulmonary system, such as by propellant based metered dose inhalers ordry powders inhalation devices. Other dosage forms are potentiallypossible such as administration transdermally, via patch mechanisms orointment.

Formulations suitable for oral administration can include (a) liquidsolutions, such as a pharmaceutically effective amount of the compounddissolved in diluents, such as water, saline, or orange juice; (b)capsules, sachets, tablets, lozenges, and troches, each containing apredetermined pharmaceutically effective amount of the activeingredient, as solids or granules; (c) powders; (d) suspensions in anappropriate liquid; and (e) suitable emulsions. Liquid formulations mayinclude diluents, such as water and alcohols, for example, ethanol,benzyl alcohol, propylene glycol, glycerin, and the polyethylenealcohols, either with or without the addition of a pharmaceuticallyacceptable surfactant, suspending agent, or emulsifying agent. Capsuleforms can be of the ordinary hard- or soft-shelled gelatin typecontaining, for example, surfactants, lubricants, and inert fillers,such as lactose, sucrose, calcium phosphate, and corn starch. Tabletforms can include one or more of the following: lactose, sucrose,mannitol, corn starch, potato starch, alginic acid, microcrystallinecellulose, acacia, gelatin, guar gum, colloidal silicon dioxide,croscarmellose sodium, talc, magnesium stearate, calcium stearate, zincstearate, stearic acid, and other excipients, colorants, diluents,buffering agents, disintegrating agents, moistening agents,preservatives, flavoring agents, and pharmacologically compatiblecarriers. Lozenge forms can comprise the active ingredient in a flavor,usually sucrose and acacia or tragacanth, as well as pastillescomprising the active ingredient in an inert base, such as gelatin andglycerin, or sucrose and acadia, emulsions, and gels containing, inaddition to the active ingredient, such carriers as are known in theart.

Formulations suitable for parenteral administration include aqueous andnon-aqueous, isotonic sterile injection solutions, which can containanti-oxidants, buffers, bacteriostats, and solutes that render theformulation isotonic with the blood of the patient, and aqueous andnon-aqueous sterile suspensions that can include suspending agents,solubilizers, thickening agents, stabilizers, and preservatives.

The compound can be administered in a physiologically acceptable diluentin a pharmaceutically acceptable carrier, such as a sterile liquid ormixture of liquids, including water, saline, aqueous dextrose andrelated sugar solutions, an alcohol, such as ethanol, isopropanol, orhexadecyl alcohol, glycols, such as propylene glycol or polyethyleneglycol such as poly(ethyleneglycol) 400, glycerol ketals, such as2,2-dimethyl-1,3-dioxolane-4-methanol, ethers, an oil, a fatty acid, afatty acid ester or glyceride, or an acetylated fatty acid glyceridewith or without the addition of a pharmaceutically acceptablesurfactant, such as a soap or a detergent, suspending agent, such aspectin, carbomers, methylcellulose, hydroxypropylmethylcellulose, orcarboxymethylcellulose, or emulsifying agents and other pharmaceuticaladjuvants.

Oils, which can be used in parenteral formulations, include petroleum,animal, vegetable, or synthetic oils. Specific examples of oils includepeanut, soybean, sesame, cottonseed, corn, olive, petrolatum, andmineral. Suitable fatty acids for use in parenteral formulations includeoleic acid, stearic acid, and isostearic acid. Ethyl oleate andisopropyl myristate are examples of suitable fatty acid esters. Suitablesoaps for use in parenteral formulations include fatty alkali metal,ammonium, and triethanolamine salts, and suitable detergents include (a)cationic detergents such as, for example, dimethyldialkylammoniumhalides, and alkylpyridinium halides, (b) anionic detergents such as,for example, alkyl, aryl, and olefin sulfonates, alkyl, olefin, ether,and monoglyceride sulfates, and sulfosuccinates, (c) nonionic detergentssuch as, for example, fatty amine oxides, fatty acid alkanolamides, andpolyoxyethylene polypropylene copolymers, (d) amphoteric detergents suchas, for example, alkyl .beta.-aminopropionates, and 2-alkylimidazolinequaternary ammonium salts, and (e) mixtures thereof.

The parenteral formulations typically contain from about 0.5% to about25% by weight of the active ingredient in solution. Suitablepreservatives and buffers can be used in such formulations. In order tominimize or eliminate irritation at the site of injection, suchcompositions may contain one or more nonionic surfactants having ahydrophile-lipophile balance (HLB) of from about 12 to about 17. Thequantity of surfactant in such formulations ranges from about 5% toabout 15% by weight. Suitable surfactants include polyethylene sorbitanfatty acid esters, such as sorbitan monooleate and the high molecularweight adducts of ethylene oxide with a hydrophobic base, formed by thecondensation of propylene oxide with propylene glycol.

Pharmaceutically acceptable excipients are also well-known to those whoare skilled in the art. The choice of excipient will be determined inpart by the particular compound, as well as by the particular methodused to administer the composition. Accordingly, there is a wide varietyof suitable formulations of the pharmaceutical composition of thepresent invention. The following methods and excipients are merelyexemplary and are in no way limiting. The pharmaceutically acceptableexcipients preferably do not interfere with the action of the activeingredients and do not cause adverse side-effects. Suitable carriers andexcipients include solvents such as water, alcohol, and propyleneglycol, solid absorbants and diluents, surface active agents, suspendingagent, tableting binders, lubricants, flavors, and coloring agents.

The compounds of the present invention, alone or in combination withother suitable components, can be made into aerosol formulations to beadministered via inhalation. These aerosol formulations can be placedinto pressurized acceptable propellants, such asdichlorodifluoromethane, propane, and nitrogen. Such aerosolformulations may be administered by metered dose inhalers. They also maybe formulated as pharmaceuticals for non-pressured preparations, such asin a nebulizer or an atomizer.

The formulations can be presented in unit-dose or multi-dose sealedcontainers, such as ampules and vials, and can be stored in afreeze-dried (lyophilized) condition requiring only the addition of thesterile liquid excipient, for example, water, for injections,immediately prior to use. Extemporaneous injection solutions andsuspensions can be prepared from sterile powders, granules, and tablets.The requirements for effective pharmaceutically acceptable carriers forinjectable compositions are well known to those of ordinary skill in theart. See Pharmaceutics and Pharmacy Practice, J.B. Lippincott Co.,Philadelphia, Pa., Banker and Chalmers, Eds., 238-250 (1982) and ASHPHandbook on Injectable Drugs, Toissel, 4th ed., 622-630 (1986).

Formulations suitable for topical administration include pastillescomprising the active ingredient in an inert base, such as gelatin andglycerin, or sucrose and acacia, as well as creams, emulsions, and gelscontaining, in addition to the active ingredient, such carriers as areknown in the art. Furthermore, transdermal patches can be prepared usingmethods known in the art.

Additionally, formulations suitable for rectal administration may bepresented as suppositories by mixing with a variety of bases such asemulsifying bases or water-soluble bases. Formulations suitable forvaginal administration may be presented as pessaries, tampons, creams,gels, pastes, foams, or spray formulas containing, in addition to theactive ingredient, such carriers as are known in the art to beappropriate.

One skilled in the art will appreciate that suitable methods ofadministering a compound of the present invention to an patient areavailable, and, although more than one route can be used to administer aparticular compound, a particular route can provide a more immediate andmore effective reaction than another route.

Useful embodiments of pharmaceutical dosage forms for administration ofthe compounds according to the present invention can be illustrated asfollows.

A large number of hard-shell capsules are prepared by filling standardtwo-piece hard gelatine capsules each with 100 mg of powdered activeingredient, 150 mg of lactose, 50 mg of cellulose and 6 mg of magnesiumstearate.

A mixture of active ingredient in a digestible oil such as soybean oil,cottonseed oil or olive oil is prepared and injected by means of apositive displacement pump into molten gelatin to form soft gelatincapsules containing 100 mg of the active ingredient. The capsules arewashed and dried. The active ingredient can be dissolved in a mixture ofpolyethylene glycol, glycerin and sorbitol to prepare a water misciblemedicine mix.

A large number of tablets are prepared by conventional procedures sothat the dosage unit is 100 mg of active ingredient, 0.2 mg of colloidalsilicon dioxide, 5 mg of magnesium stearate, 275 mg of microcrystallinecellulose, 11 mg of starch, and 98.8 mg of lactose.

Appropriate aqueous and non-aqueous coatings may be applied to increasepalatability, improve elegance and stability or delay absorption.

Immediate release tablets/capsules are solid oral dosage forms made byconventional and novel processes. These units are taken orally withoutwater for immediate dissolution and delivery of the medication. Theactive ingredient is mixed in a liquid containing ingredient such assugar, gelatin, pectin and sweeteners. These liquids are solidified intosolid tablets or caplets by freeze drying and solid state extractiontechniques. The drug compounds may be compressed with viscoelastic andthermoelastic sugars and polymers or effervescent components to produceporous matrices intended for immediate release, without the need ofwater.

Moreover, the compounds of the present invention can be administered inthe form of nose drops, or metered dose and a nasal or buccal inhaler.The drug is delivered from a nasal solution as a fine mist or from apowder as an aerosol.

In one embodiment, the teachings of the present disclosure provide forthe use of such pharmaceutical compositions and medicaments in a methodof treating a viral infection or treating a disease state and/orcondition caused by or related to such viral infection. In oneembodiment, the treatment is the result of the inhibition of a viral RNAor DNA polymerase, such as but not limited to a RdRp. Such treatment orinhibition need not be complete to be useful. The method of treatmentcomprises the steps of: (i) identifying a patient in need of suchtreatment; (ii) providing such pharmaceutical composition containing atleast one compound of the invention; and (iii) administering suchpharmaceutical composition in a therapeutically effective amount totreat the viral infection in a patient in need of such treatment or toinhibit the activity of a viral RNA or DNA polymerase in a patient inneed of such treatment.

In one embodiment, the teachings of the present disclosure provide forthe use of such pharmaceutical compositions and medicaments in a methodof preventing or suppressing a viral infection or preventing orsuppressing a disease state and/or condition caused by or related tosuch viral infection. In one embodiment, the prevention or suppressionis the result of the inhibition of a viral RNA or DNA polymerase, suchas but not limited to a R^(d)R^(p). Such prevention, suppression orinhibition need not be complete to be useful. The method of preventingor suppressing can optionally comprises the steps of: (i) identifying apatient in need of such prevention; (ii) providing such pharmaceuticalcomposition containing at least one compound of the general Formula I;and (iii) administering such pharmaceutical composition in atherapeutically effective amount to prevent or suppress the viralinfection in a patient in need of such treatment or to inhibit theactivity of a viral RNA and DNA polymerase in a patient in need of suchtreatment.

The methods of the treating and preventing a viral infection or adisease state and/or condition caused by or related to said viralinfection may further comprise administering a therapeutically effectiveamount of a compound of the present invention in combination with atherapeutically effective amount of another anti-viral agent which, inparticular, may be active against HCV. Agents active against HCVinclude, but are not limited to, ribavirin, levovirin, viramidine,thymosin alpha-1, an inhibitor of HCV NS3 serine protease, an inhibitorof inosine monophosphatedehydrognease, interferon-α, pegylatedinterferon-α (peginterferon-α), a combination of interferon-α andribavirin, a combination of peginterferon-α and ribavirin, a combinationof interferon-α and levovirin, and a combination of peginterferon-α andlevovirin. Interferon-α includes, but is not limited to, recombinantinterferon-α2a, interferon-alb, a consensus interferon, and a purifiedinterferon-α product.

The compounds and pharmaceutical compositions of the present disclosurecan be administered to patients to prevent and/or treat a number ofcancers. Cancers include, but are not limited to, leukemias andlymphomas such as acute lymphocytic leukemia, acute nonlymphocyticleukemias, chronic lymphocytic leukemia, chronic myelogenous leukemia,Hodgkin's Disease, non-Hodgkin's lymphomas, and multiple myeloma,childhood solid tumors such as brain tumors, neuroblastoma,retinoblastoma, Wilms Tumor, bone tumors, and soft-tissue sarcomas,common solid tumors of adults such as lung cancer, colon and rectumcancer, breast cancer, prostate cancer, urinary cancers, uterinecancers, oral cancers, pancreatic cancer, melanoma and other skincancers, stomach cancer, ovarian cancer, brain tumors, liver cancer,laryngeal cancer, thyroid cancer, esophageal cancer, and testicularcancer. The cancer may be related to a viral infection or an activity ofa viral DNA or RNA polymerase.

The methods of the treating and preventing cancer may also comprisesfurther administering of a chemotherapeutic agent in combination withany of the compounds or pharmaceutical compositions of the presentdisclosure. Any suitable chemotherapeutic agent can be employed for thispurpose. The chemotherapeutic agent is typically selected from the groupconsisting of alkylating agents, antimetabolites, natural products,hormonal agents, and miscellaneous agents.

Examples of alkylating chemotherapeutic agents include carmustine,chlorambucil, cisplatin, lomustine, cyclophosphamide, melphalan,mechlorethamine, procarbazine, thiotepa, uracil mustard,triethylenemelamine, busulfan, pipobroman, streptozocin, ifosfamide,dacarbazine, carboplatin, and hexamethylmelamine.

Examples of chemotherapeutic agents that are antimetabolites includecytosine arabinoside, fluorouracil, gemcitabine, hydroxyurea,mercaptopurine, methotrexate, azaserine, thioguanine, floxuridine,fludarabine, cladribine and L-asparaginase.

Examples of chemotherapeutic agents that are natural products includeactinomycin D, bleomycin, camptothecins, daunomycin, doxorubicin,etoposide, mitomycin C, TAXOL™ (paclitaxel), taxotere, teniposide,vincristine, vinorelbine, mithramycin, idarubicin, MITHRACIN™.(plicamycin), and deoxycoformycin.

An example of a hormonal chemotherapeutic agent includes tamoxifen.Examples of the aforesaid miscellaneous chemotherapeutic agents includemitotane, mitoxantrone, vinblastine, and levamisole.

The ability of a compound to inhibit viral polymerases can be evaluatedusing known assays. The ability of a compound to inhibit HCV NS5Bpolymerase can be evaluated using the following assay.

HCV NS5B Polymerase Assay

Antiviral activity of the test compounds was assessed (Okuse et al.,Antiviral Res. 2005, 65, 23-34) in the stably HCV RNA-replicating cellline, AVA5, derived by transfection of the human hepatoblastoma cellline, Huh7 (Blight et al., Sci. 2000, 290, 1972). Compounds were addedto dividing cultures once daily for three days. Media was changed witheach addition of compound. Cultures generally started the assay at30-50% confluence and reached confluence during the last day oftreatment. Intracellular HCV RNA levels and cytotoxicity were assessed24 hours after the last dose of compound.

Triplicate cultures for HCV RNA levels (on 48-well and 96-well plates)and cytotoxicity (on 96-well plates) were used. A total of six untreatedcontrol cultures, and triplicate cultures treated with α-interferon andribavirin served as positive antiviral and toxicity controls.

Intracellular HCV RNA levels were measured using a conventional blothybridization method in which HCV RNA levels are normalized to thelevels of B-actin RNA in each individual culture (Okuse et al., Antivir.Res. 2005, 65, 23-34). Cytotoxicity was measured using a neutral red dyeuptake assay (Korba and Gerin, Antivir. Res. 1992, 19, 55). HCV RNAlevels in the treated cultures are expressed as a percentage of the meanlevels of RNA detected in untreated cultures.

A representative compound of Formula I demonstrated significant activityin this assay.

Compound Synthesis

Compounds of Formula I can be prepared using synthetic intermediates andsynthetic procedures that are known, or they can be prepared using thesynthetic intermediates and synthetic procedures described herein, forexample, as described in the following Schemes.

The following abbreviations are used herein.

-   -   Tr: trityl    -   Bn: benzyl    -   TBDPS: tert-butyldiphenylsilyl    -   m-CPBA: 3-chloroperoxybenzoic acid    -   TFA: trifluoroacetic acid    -   TBDMSCl: tert-butyldimethylsilyl chloride    -   DMF: dimethylformamide    -   THF: tetrahydrofuran    -   LDA: lithium diisopropylamine    -   TEAB: triethylammonium bicarbonate    -   MmTrCl: monomethoxytrityl chloride    -   MMTrCl: monomethoxytrityl chloride    -   DMAP: dimethylaminopyridine    -   DEAE: diethylaminoethyl-sepharose    -   CMA-80: Chloroform 80: MeOH 18: NH₄OH: 2    -   CMA-50: Chloroform 50: MeOH 40: NH₄OH: 10    -   Bz: benzoyl    -   BnBr: benzyl bromide    -   LiHMDS: lithium hexamethyldisalazane    -   TBDPSCl: tert-butyldiphenylsilyl chloride    -   DMSO: dimethylsulfoxide    -   RMgBr: alkyl magnesium bromide    -   DIBAL: diisobutylaluminum hydride    -   DBN: 1,5-diazabicyclo[4.3.0]non-5-ene    -   DBU: 1,8-diazabicyclo[5.4.0]undec-7-ene    -   MeMgBr: methylmagnesium bromide    -   P: Represents a suitable protecting group    -   R: In Schemes 41-86 R can have any of the values defined for R²        herein

The invention will now be illustrated by the following non-limitingExamples.

Example 1 Synthesis of 40p

To a solution of tricyclic product (40o, 0.1 g, 0.27 mmol) in methanol(2 mL) was added aqueous 1 N HCl (2 mL) and stirred at room temperatureovernight. The reaction mixture was concentrated in vacuo to dryness.The residue obtained was triturated with methanol/ether and the solidobtained was collected by filtration washed with ether and dried invacuo at acetone reflux temperature to furnish 40p (0.08 g, 90%) as ayellow solid; MP 240-242° C. ¹H NMR (300 MHz, DMSO-d₆) δ 11.39-10.93 (m,1H), 8.04 (s, 1H), 7.12 (d, J=11.9, 1H), 7.00 (s, 1H), 6.09 (s, 3H),5.76 (d, J=11.9, 1H), 5.31 (s, 1H), 3.76 (d, J=10.6, 2H), 3.68 (s, 2H),0.84 (s, 3H); MS (ES) 330.9.

The intermediate 40o was prepared as follows.

a. To a stirred solution of freshly distilled pyrrole (6.79 g, 100.89mmol) in diethyl ether (100 mL) was added ethyl magnesium bromide (33.6mL, 100.89 mmol, 3M solution in ether) slowly at 20° C. The reactionmixture was further stirred at 20° C. for 1 h and the solvent wasremoved under vacuum to give 40b. To 40b in dichloromethane (500 mL) at0° C. was added a solution of 40c (WO 2006/050161, 10.96 g, 25.22 mmol)in dichloromethane (100 mL) and further stirred at 4° C. for 72 h. Thereaction mixture was quenched by adding saturated solution of ammoniumchloride (200 mL) and organic layer was separated. The aqueous layer wasfurther extracted with dichloromethane (2×200 mL). The combined organicextracts were washed with water (2×50 mL) and brine (1×50 mL) and dried.After filtration, the filtrate containing 40d was treated withtrifluoroacetic acid (4.14 g, 36.34 mmol) at 20° C. and stirred for 14h. The reaction mixture was washed with water (2×100 mL) and brine (1×50mL) and dried. After filtration, the filtrate was concentrated to give12.5 g of crude 40e.NOTE: THF was also used to make Grignard reagent instead of diethylether. THF was removed by distillation and the traces by azeotropingwith toluene.b. Phosphorusoxy chloride (19.33 g, 126.1 mmol) was added toN,N-dimethylformamide (100 mL) at 0° C. and stirred for 30 min. To thissolution was added 40e (12.1 g, 25.22 mmol) in dichloromethane (50 mL)slowly over a period of 15 min. at 0° C. and stirring was continued for1 h. The reaction mixture was quenched by adding saturated solution ofsodium acetate (100 mL) and stirred for 30 min. The reaction mixture wasconcentrated to remove dichloromethane and the residue was diluted withethyl acetate (200 mL). The organic layer was separated and washed withwater (2×100 mL) and brine (1×50 mL) and dried. After filtration, thefiltrate was concentrated and the residue was purified by flashchromatography using ethyl acetate in hexanes (0 to 12%) to give 2.92 g(22.6% from 40c) of 40f as dark brown syrup. MS (ES⁻): 510.2.NOTE: Only DMF was also used as solvent; there was no need ofdichloromethane. For workup, 2N NaOH was used in place of sodiumacetate.c. To a stirred solution of above obtained 40f (2.5 g, 4.88 mmol) intetrahydrofuran (50 mL) was added sodium hydride (0.39 g, 9.77 mmol, 60%dispersion in mineral oil) at 0° C. After stirring for 30 min at 0° C.,O-(mesitylsulfonyl)hydroxylamine (40 g, 1.15 g, 5.37 mmol, prepared bythe method of Krause, J. G. Synthesis, 1972, 140) was added at 0° C. andfurther stirred for 2 h. The reaction mixture was quenched by addingwater (20 mL) and extracted with ethyl acetate (2×50 mL). The combinedorganic extracts were washed with water (2×25 mL) and brine (1×25 mL)and dried. After filtration, the filtrate was concentrated to give 2.75g of 1 h as dark syrup. MS (ES⁺): 527.43.

The compound 40h can also be prepared as follows.

d. Aldehyde 40f (5.2 Kg, 10.16 moles) was dissolved in methyl tert-butylether (72.8 L) and charged into a clean SS reactor (600 L). Aliquot 336(0.25 Kg, 0.61 mole) and ammonium chloride (6.53 Kg, 122.07 moles) wereadded to the reactor and reaction mixture was cooled to 0-5° C. Ammoniumhydroxide (19.08 L, 137 moles, 28% solution in water) was added at 0-5°C. followed by addition of a cold (0-5° C.) sodium hydroxide solution(16.59 Kg in 66 L water, 414.75 moles) at the same temperature over aperiod of 3 h. Sodium hypochlorite (251 L, 222.58 moles, 6% solution)addition was started at 0° C. and during the addition the temperaturewas allowed to rise to 15° C. The reaction mixture was further stirredat room temperature for 2 h. TLC showed completion of the reaction.Ethyl acetate (104 L) was added to the reaction mixture and layers wereseparated. The aqueous layer was re-extracted with ethyl acetate (2×104L). The combined organic layers were washed with water (52 L), sodiumthiosulfate (2×156 L, 10% solution), water (52 L) and brine (70 L) anddried over sodium sulfate (10.4 Kg). After filtration, the filtrate wasconcentrated under vacuum below 40° C. to afford crude compound 40h (4.4kg) as dark syrup.e. To a stirred solution of 40h (2.56 g, 4.88 mmol) in dioxane (50 mL)was added water (15 mL) and cooled to 0° C. To this cooled solution at0° C. was added hydroxylamine-O-sulfonic acid (1.93 g, 17.10 mmol).After stirring for 1 h, a cold solution of potassium hydroxide (2.19 g,39.0 mmol) in water and dioxane (20 mL+20 mL) was added and furtherstirred at 0° C. for 1 h. The reaction mixture was diluted with ethylacetate (100 mL), the organic layer was separated and washed with water(2×50 mL) and brine (1×50 mL) and dried. After filtration, the filtratewas concentrated to afford 2.6 g of 40i, which was used as such for thenext step.f. To a stirred solution of 40i (2.55 g, 4.88 mmol) inN,N-dimethylacetamide (70 mL) was added formamidine acetate (5.08 g,48.88 mmol) and the reaction mixture was stirred at 140° C. for 3 h.Most of the N,N-dimethylacetamide was removed under vacuum and theresidue was suspended in water (100 mL), which was extracted with ethylacetate (2×250 mL). The combined organic extracts were washed with water(50 mL) and brine (50 mL) and dried. After filtration, the filtrate wasconcentrated and the residue was purified by flash chromatography usinga mixture of ethyl acetate and methanol (9:1) in hexanes (0 to 30%) toprovide impure compound (1.25 g). Further purification by chromatographyon silica gel gave 0.48 g (17.8% from 40f) of 40j as a light brownsolid. ¹H NMR (CDCl₃): δ 7.87 (s, 1H), 7.43-7.21 (m, 15H), 6.88 (d,J=4.5 Hz, 1H), 6.50 (d, J=4.5 Hz, 1H), 5.87 (s, 1H), 5.36 (b, 2H, D₂Oexchangeable), 4.83 (dd, J=31.8, 12.2 Hz, 2H), 4.68-4.52 (m, 4H),4.40-4.35 (m, 1H), 4.04 (d, J=8.8 Hz, 1H), 3.88 (dd, J=10.9, 2.3 Hz,1H), 3.69 (dd, J=11.1, 3.6 Hz, 1H), 1.00 (s, 3H). MS (ES⁺): 551.40.NOTE: Acetic acid and n-BuOH can also be used as solvent in place ofdimethyl acetamide.g. To a stirred solution of 40j (0.27 g, 0.484 mmol) in dichloromethane(25 mL) was added boron trichloride (4.84 mL, 4.84 mmol, 1M solution indichloromethane) at −40° C. and the mixture was further stirred at −40°C. for 30 min and slowly brought to 0° C. in about 30 min and stirred at0° C. for 20 min. The reaction was quenched by adding ethyl alcohol (50mL) and concentrated under reduced pressure. Again, ethyl alcohol (50mL) was added and concentrated. This operation was repeated 4 times.After concentration, the residue was dissolved in mixture of isopropylalcohol and methanol (20 and 2 mL) and methanol was removed byconcentration under vacuum. Solid separated out, which was collected byfiltration and dried at 60° C. under vacuum to provide 39 mg (25%) of40k as a colorless solid. ¹H NMR (300 MHz, DMSO-d₆): δ 9.71 (bs, 1H, D₂Oexchangeable), 8.99 (bs, 1H, D₂O exchangeable), 8.16 (s, 1H), 7.41 (d,J=4.5 Hz, 1H), 6.97 (d, J=4.7 Hz, 1H), 5.34 (s, 1H), 4.8-4.0 (m, 3H, D₂Oexchangeable), 3.81-3.56 (m, 4H), 0.79 (s, 3H). MS (ES⁺): 281.6.

Compound 40k can also be prepared as follows.

h. To a solution of compound 40j (128 g) in methanol (1.4 L), conc. HCl(130 mL) was added followed by 10% Pd/C (12 g) and the mixture washydrogenated at 70 psi for 10 h. Since the compound precipitated out ofthe solution, water (500 mL) was added to the mixture and heated at 60°C. for about 1 h and filtered through a Celite pad. The Celite pad withpalladium was re-suspended in a mixture of water (400 mL) and methanol(400 mL) and heated at 60° C. for about 1 h and again filtered throughCelite. This operation was repeated until there was no compound leftun-dissolved. The combined filtrates were concentrated under vacuum andrecrystallized from water and ethanol (1:20) to afford 32.5 g of thedesired product 40k as pale yellow crystals. The mother liquor wasconcentrated and recrystallized again to afford another crop of 5.6 g.i. To a suspension of 40k (0.962 g, 3.4 mmol) in DMF (30 mL) and acetone(30 mL) was added 2,2-dimethoxypropane (4.2 mL, 98%, 34 mmol) and p-TsOH(650 mg, 98.5%, 3.4 mmol) and stirred at room temperature for 3 days.The reaction mixture was neutralized with 2N NaOH (aq.) and concentratedin vacuo to dryness. The residue was taken in water (90 mL) andextracted with ethyl acetate (3×30 mL). The organic layers were combineddried, filtered and concentrated in vacuo to dryness. The residueobtained was purified by flash column chromatography (silica gel, 40 g,eluting with 0-100% CMA 80 in chloroform) to give 40l (360 mg, 33%) as ayellow solid. ¹H NMR (300 MHz, DMSO-d₆) δ 7.83 (s, 1H), 7.67 (s, 2H),6.87 (d, J=4.5, 1H), 6.63 (d, J=4.4, 1H), 5.54 (s, 1H), 4.97 (t, J=5.7,1H), 4.37 (d, J=2.4, 1H), 4.03-3.95 (m, 1H), 3.57 (dd, J=5.4, 9.7, 2H),1.55 (s, 3H), 1.33 (s, 3H), 1.15 (s, 3H).j. To a solution of 40l (375 mg, 1.2 mmol) in DMF (10 mL) was addediodosuccinimide (290 mg, 1.3 mmol) and stirred at room temperatureovernight. The reaction mixture was diluted with water (30 mL) andextracted with ethyl acetate (3×25 mL). The organic layers were combinedwashed with water (25 mL), brine (25 mL), dried, filtered, andconcentrated in vacuo. The residue obtained was purified by flash columnchromatography (silica gel 12 g, eluting with 0-100% CMA 80 inchloroform) to give 40m (0.44 g, 83%) as an off white solid; MP 88-91°C. ¹H NMR (300 MHz, DMSO-d₆) δ 7.88 (s, 1H), 6.91 (s, 1H), 5.50 (s, 1H),4.98 (t, J=5.9, 1H), 4.38 (d, J=2.5, 1H), 4.02 (ddd, J=2.3, 4.7, 7.2,1H), 3.63-3.52 (m, 2H), 1.54 (s, 3H), 1.33 (s, 3H), 1.10 (s, 3H); MS(ES) 444.83.k. To a solution of 40m (2.6 g, 5.8 mmol) in DMF (70 mL) was addedcopper iodide (440 mg, 2.3 mmol), methyl acrylate (22.7 ml, 252 mmol),triethylamine (3.5 mL, 25.2 mmol) andtetrakis(triphenylphosphine)Palladium (1.85 g, 1.16 mmol) and heatedwith stirring at 70° C. for 3 days. The reaction was diluted with water(90 mL) and extracted with ethyl acetate (3×70 mL). The organic layerswere combined washed with water (70 mL); brine (70 mL) dried, filtered,and concentrated in vacuo to dryness. The residue obtained was purifiedby flash column chromatography (silica gel 110 g, eluting with 0-100%9:1 EtOAc:MeOH in hexane) to give 40n (0.43 g, 18%) as a yellow solid.¹H NMR (300 MHz, DMSO-d₆) δ 8.05 (d, J=15.4, 1H), 7.94 (s, 1H), 7.61 (s,2H), 7.27 (s, 1H), 6.45 (d, J=15.3, 1H), 5.52 (s, 1H), 4.96 (t, J=6.0,1H), 4.40 (d, J=2.4, 1H), 4.07-4.00 (m, 1H), 3.71 (s, 3H), 3.65-3.57 (m,2H), 1.55 (s, 3H), 1.34 (s, 3H), 1.13 (s, 3H); MS (ES) 402.8.l. To a freshly prepared solution of sodium methoxide (69 mg sodium in30 ml methanol, 0.1 M) in methanol was added 40n (0.29 g, 0.72 mmol) andheated with stirring at reflux for 4 h and then at room temperatureovernight. The reaction mixture neutralized with glacial acetic acid(0.18 mL) and the solid obtained was collected by filtration washed withmethanol and dried in vacuo to furnish tricyclic product (40o, 0.126 g,47%) as a yellow solid: ¹H NMR (300 MHz, DMSO-d₆) δ 11.15 (s, 1H), 8.04(s, 1H), 7.14 (d, J=11.9, 1H), 6.91 (s, 1H), 5.77 (d, J=11.9, 1H), 5.44(s, 1H), 5.01 (t, J=5.5, 1H), 4.41 (d, J=2.3, 1H), 4.05 (td, J=2.3, 4.9,1H), 3.58 (dt, J=5.6, 11.5, 2H), 1.55 (s, 3H), 1.34 (s, 3H), 1.12 (s,3H); MS (ES) 370.9 (100%, M−1).

Example 2 Synthesis of 87j

A solution of 87i (90 mg, 0.2 mmol) in methanol (1 mL) was added to asolution of freshly prepared NaOMe solution in methanol (0.17 M, 5 mL,0.84 mmol) and stirred at room temperature overnight. The reactionmixture was neutralized by acetic acid (0.5 mL) and concentrated invacuo. The residue obtained was purified by flash column chromatography(silica gel, 5 g, eluting with 0 to 100% CMA80 in chloroform) to yield87j (27 mg, 48%) as a bright yellow solid; mp 212° C. ¹H NMR (300 MHz,DMSO-d₆) 7.51 (s, 1H), 6.53 (s, 1H), 6.37 (s, 2H), 5.12 (s, 1H), 5.01(d, J=6.9 Hz, 1H), 4.79 (s, 1H), 4.74 (t, J=5.4 Hz, 1H), 3.84-3.67 (m,2H), 3.60 (dd, J=4.7, 10.4 Hz, 2H), 3.36 (s, 3H), 0.86 (s, 3H). MS (ES⁺)335.1.

The intermediate 87i was prepared as follows:

a. To a solution of 40i (11.1 g, 21.3 mmol) in EtOH (500 mL) was addedconc. NH₄OH (28-30%, 200 mL) followed by dropwise addition of H₂O₂ (30%in H₂O, 7.2 mL). After the addition, the reaction mixture was stirred atroom temperature overnight and concentrated in vacuo to dryness. Theresidue obtained was dissolved in chloroform (500 mL) washed with water,brine, dried, filtered and the filtrate was concentrated in vacuo todryness. The residue obtained was purified by flash columnchromatography (silica gel 300 g, eluting with 0-100%, ethyl acetate inhexane) to furnish 87a (3.45 g, 30%) as a brown oil. ¹H NMR (300 MHz,DMSO-d₆/D₂O) δ 7.45-7.26 (m, 15H), 6.67 (d, j=4.3, 1H), 6.02 (d, J=4.3,1H), 5.29 (s, 1H), 4.66-4.55 (m, 6H), 4.15 (s, 1H), 3.92 (d, j=6.6, 1H),3.73 (m, 2H), 1.10 (s, 3H); MS (ES⁺): 542.2.b. To a solution of 87a (3 g, 5.5 mmol) in triethyl orthoformate (60 mL)was added TFA (0.43 mL, 5.5 mmol) and heated at 80° C. for 45 min. Thereaction mixture was concentrated in vacuo to dryness and the residueobtained was purified by flash column chromatography (silica gel,eluting with hexanes/EtOAc, 1:0 to 1:1) to furnish 87b (1.783 g, 58.4%)as a light brown syrup. ¹H NMR (300 MHz, DMSO-d₆): δ 11.70 (bs, 1H),7.90 (d, J=3.1 Hz, 1H), 7.43-7.24 (m, 15H), 6.85 (d, J=4.4 Hz, 1H), 6.67(d, J=4.4 Hz, 1H), 5.57 (s, 1H), 4.80-4.56 (m, 6H), 4.27-4.13 (m, 1H),4.01-3.96 (m, 1H), 3.82 (dd, J=2.6, 11.0 Hz, 1H), 3.70 (dd, J=4.3, 11.0Hz, 1H), 1.07 (s, 3H); MS (ES): 550.0.c. To a solution of 87b (3.8 g, 6.9 mmol) in methanol (100 mL) was addedPd on carbon (10%, 580 mg) and conc. HCl (3 mL). The reaction mixturewas hydrogenated at 50 psi for 4 h. The reaction mixture was filteredthrough a pad of Celite and the filtrate was concentrated in vacuo todryness to furnish 87c (2.18 g, 100%) as brown syrup which was pureenough to be used as such for next step. MS (ES+): 282.1; (ES−): 280.4.d. To a solution of 87c (2.18 g, 7.75 mmol) in pyridine (30 mL) wasadded acetic anhydride (6.5 mL, 69 mmol), DMAP (10 mg) and stirred at70° C. overnight. The reaction mixture was cooled to room temperature,diluted with water (50 mL) and ethyl acetate (50 mL). The aqueous layerwas separated and extracted with ethyl acetate (50 mL). The organiclayers were combined, washed with water (50 mL), brine (50 mL), driedand concentrated in vacuo to dryness. The residue obtained was purifiedby flash column chromatography (silica gel 80 g, eluting with methanolin chloroform 0-20%) to afford 87d (1.88 g, 70%) as off white solid, MP147-154° C. ¹H NMR (300 MHz, DMSO-d₆): δ 11.78 (s, 1H), 8.32 (s, 1H),7.93 (s, 1H), 6.93 (d, J=4.4 Hz, 1H), 6.62 (d, J=4.4 Hz, 1H), 5.60 (s,1H), 5.20 (d, J=4.1 Hz, 1H), 4.47-4.32 (m, 1H), 4.21 (dd, J=7.8, 19.6Hz, 111), 2.70 (s, 6H), 2.01 (s, 3H), 1.87 (s, 3H); MS (ES⁺): 430.0(M+Na).e. To a solution of 87d (1.08 g, 2.66 mmol) in dichloromethane (75 mL)at 0° C. was added N-iodosuccinimide (719.2 mg, 3.2 mmol). The reactionwas allowed to warm to room temperature overnight and concentrated invacuo. The residue obtained was purified by flash column chromatography(silica gel 40 g, eluting with 0 to 100% ethyl acetate in hexane) toafford 87e (1.09 g, 77%) as an orange solid; mp 212° C. ¹H NMR (300 MHz,DMSO-d₆) δ 11.83 (s, 1H), 7.94 (s, 1H), 6.81 (s, 1H), 5.56 (s, 1H), 5.17(d, J=4.2 Hz, 1H), 4.35 (s, 1H), 4.20 (d, J=11.7 Hz, 2H), 2.07 (d, J=2.2Hz, 611), 2.00 (s, 3H), 1.39 (s, 3H).f. To hot refluxing pyridine (14 mL) was added a solution of 87e (1.09g, 2.04 mmol) in pyridine (2 mL) and copper cyanide (2.15 g, 24 mmol).The reaction mixture was heated at reflux overnight, cooled to roomtemperature and diluted with water (50 mL) and ethyl acetate (50 mL).The insoluble inorganic impurities were removed by filtration; theaqueous layer was separated and extracted with ethyl acetate (2×100 mL).The organic layers were combined washed with brine (100 mL), dried,filtered, and concentrated in vacuo. The residue obtained was purifiedby flash column chromatography (silica gel, 20 g, eluting with 10 to 90%[9:1] of ethyl acetate:methanol in hexane) to yield 87f (270 mg, 31%) asa colorless oil. ¹H NMR (300 MHz, DMSO-d₆) δ 12.48 (s, 1H), 8.16 (s,1H), 7.21 (s, 1H), 5.56 (s, 1H), 5.17 (s, 1H), 4.35 (s, 1H), 4.17 (s,2H), 2.07 (s, 6H), 1.99 (s, 3H), 1.38 (s, 3H).g. A solution of 87f (460 mg, 1.06 mmol) in phosphorous oxychloride (10mL) was heated at reflux temperature for 2 h. The reaction was cooledwith ice water, quenched with ice water and stirred vigorously until allphosphorous oxychloride was destroyed. This aqueous layer was extractedwith ethyl acetate (3×100 mL). The organic layers were combined washedwith brine (100 mL), dried, filtered, and concentrated in vacuo to yield87g (653 mg).h. To a solution of crude 87g in chloroform (15 mL) and ethanol (30 mL)was added methyl hydrazine (0.1 mL, 1.74 mmol) and stirred at roomtemperature overnight. The reaction mixture was concentrated in vacuoand the residue purified by flash column chromatography (silica gel,12g, eluting with 0 to 100% [9:1] of ethyl acetate:methanol in hexane)to yield 87h (140 mg, 28%) as an yellow solid. ¹H NMR (300 MHz, DMSO-d₆)δ 8.07 (s, 111), 7.27 (s, 1H), 5.75 (s, 1H), 5.48 (s, 2H), 5.21 (d,J=4.2 Hz, 1H), 4.37 (s, 1H), 4.22 (d, J=11.6 Hz, 2H), 3.36 (d, J=11.0Hz, 3H), 2.08 (s, 611), 1.99 (s, 3H), 1.40 (s, 3H).i. To a solution of 87h (140 mg, 0.29 mmol) in ethanol (20 mL) was addedconcentrated hydrochloric acid (2 drops) and heated at refluxtemperature for 2 h. The reaction mixture was concentrated in vacuo togive 87i (90 mg, 64.3%).

Example 3 Synthesis of 88e

To a solution of 88d (1.31 g, 2.21 mmol) in MeOH (110 mL) and EtOAc (60mL) was added 1N HCl (9.5 mL), Pd/C (10%, 200 mg) and hydrogenated at 60psi for 24 h. The reaction mixture was filtered through Celite, and thefiltrate was concentrated in vacuo. The residue obtained was purified byflash column chromatography (silica gel, eluting with CMA80/CMA50 1:0 to1:1) to give 88e (489 mg) as a yellow solid. The product obtained wastriturated with water, collected by filtration and dried in vacuo tofurnish 88e (251 mg, 35%) as an off-white solid; mp 210° C. ¹H NMR (300MHz, DMSO-d₆): 11.07 (bs, 1H), 10.53 (bs, 1H), 7.70 (s, 1H), 6.18 (s,1H), 5.16 (s, 1H), 4.95 (d, J=6.1 Hz, 1H), 4.84 (t, J=5.2 Hz, 1H), 4.80(s, 1H), 3.80-3.65 (m, 3H), 3.61-3.50 (m, 1H), 0.84 (s, 3H); MS (ES⁺):322.1.

The intermediate 88d was prepared as follows:

a. To a solution of 40j (100 mg, 0.18 mmol) in CH₂Cl₂ (9 mL) cold (icewater bath) was added NBS (32 mg, 0.18 mmol) and stirred at roomtemperature for 1 h. The reaction mixture was concentrated in vacuo andthe residue obtained was purified by flash column chromatography (silicagel, eluting with chloroform/methanol, 1:0 to 20:1) to furnish 88a (102mg, 90%) as a yellow solid. ¹H NMR (300 MHz, DMSO-d₆): δ 7.89 (s, 1H),7.42-7.25 (m, 15H), 6.91 (s, 1H), 5.64 (s, 1H), 4.74 (s, 2H), 4.66-4.52(m, 4H), 4.22-4.16 (m, 1H), 4.03 (d, J=8.7 Hz, 1H), 3.90-3.68 (m, 2H),1.05 (s, 3H); MS (ES⁺): 631.3.b. A solution of 88a (35 g, 55.6 mmol) in methanol (350 mL) in a 2-Lstainless steel bomb was added triethylamine (7.7 mL, 55.6 mmol),Pd(OAc)₂ (3.5 g) and 1,1-bis(diphosphino)-ferrocene (3.5 g). The bombwas vacuum flushed and charged with CO to 150 psi. The reactor washeated with stirring at 150° C. overnight and cooled to roomtemperature. The catalyst was filtered through a pad of Celite andconcentrated in vacuo to obtain crude product. The crude was purified byflash column chromatography (silica gel 1.2 kg, eluting with ethylacetate in Hexane (0-50%, 2 L each) to give 10.7 g of 88b as yellowsemisolid. ¹H NMR (300 MHz, DMSO-d₆): δ 9.05 (s, 1H, exchangeable), 8.41(s, 1H, exchangeable), 8.07 (s, 1H), 7.49-7.20 (m, 16H), 5.66 (s, 1H),4.76 (s, 2H), 4.72-4.45 (m, 4H), 4.19 (s, 1H), 4.09-3.98 (m, 1H), 3.86(d, 8.9, 1H), 3.76 (s, 3H), 3.75-3.68 (m, 1H), 1.09 (s, 3H); MS (ES⁺):609.1.c. To a solution of 88b (8.5 g, 14 mmol) in methanol (140 mL) was addedTHF (140 mL) and 1 N NaOH (140 mL). The reaction was heated withstirring at 40° C. for 1.5 h. The reaction mixture was concentrated invacuo to remove methanol and THF. The pH was adjusted to 6 using 2.5NHCl and the aqueous layer was extracted twice with ethyl acetate (500 mLand 200 mL). The organic layers were combined, dried and concentrated invacuo to furnish crude product. The crude was purified by flash columnchromatography (silica gel 200 g, eluting with 0-50% CMA 80 inchloroform) to furnish 88c (9.5 g, 100%) as a light yellow solid; MP164° C. ¹H NMR (300 MHz, DMSO-d₆) δ 13.37-12.95 (bs, 1H), 9.42 (s, 1H),8.32 (s, 1H), 8.04 (s, 1H), 7.35 (dd, J=13.6, 23.4 Hz, 15H), 5.66 (s,1H), 4.68 (d, J=42.2 Hz, 6H), 4.18 (s, 1H), 4.01 (d, J=8.4 Hz, 1H), 3.83(s, 2H), 3.33 (s, 1H), 1.07 (s, 3H); MS (ES⁺): 595.0.d. To a solution of 88c (2 g, 3.36 mmol) in benzene (30 mL) was addedtriethylamine (0.54 mL, 3.87 mmol) and diphenyl phosphoryl azide (0.82mL, 97%, 3.68 mmol) and heated at reflux for 14 h. The reaction mixturewas cooled to room temperature and quenched with 1M NaHCO₃ (100 mL). Thereaction mixture was extracted with EtOAc (2×200 mL). The combinedorganic extracts were washed with brine (150 mL), dried, filtered andconcentrated in vacuo. The residue obtained was purified by flash columnchromatography (silica gel, chloroform/methanol, 1:0 to 20:1) to give88d (1.42 g, 71%) as a brown solid. ¹H NMR (300 MHz, DMSO-d₆): 11.17 (s,1H), 10.55 (s, 1H), 7.72 (s, 1H), 7.40-7.20 (m, 15H), 6.11 (s, 1H), 5.41(s, 1H), 4.70-4.52 (m, 6H), 4.18-4.10 (m, 1H), 3.96 (d, J=7.7 Hz, 1H),3.77-3.60 (m, 2H), 1.12 (s, 3H); MS (ES⁺): 592.1.

Example 4 Synthesis of 89c

To a solution of tricyclic product 89b (0.165 g, 0.43 mmol) in methanol(5 mL) was added aqueous 1 N HCl (5 mL) and stirred at room temperatureovernight. The reaction mixture was concentrated in vacuo to dryness.The residue obtained was purified by flash column chromatography (silicagel 12 g, eluting with 0-100% CMA 80 in chloroform) to give 89c (0.014g, 9%) as a yellow solid; mp 169° C. ¹H NMR (300 MHz, DMSO-d₆) δ8.00-7.91 (m, 1H), 7.23-7.15 (m, 1H), 6.91-6.85 (m, 1H), 5.32-5.27 (m,1H), 5.03-4.93 (m, 1H), 4.86-4.79 (m, 2H), 3.89-3.70 (m, 3H), 3.65-3.55(m, 2H), 2.00-1.93 (m, 3H), 0.87-0.79 (m, 3H); MS (ES⁻) 344.8.

The intermediate 89b was prepared as follows:

a. To a solution of 40m, (2 g, 4.5 mmol) in DMF (20 mL) was added copperiodide (17 mg, 0.9 mmol), methyl methacrylate (9.5 ml, 90 mmol),triethylamine (1.25 mL, 9 mmol) andtetrakis(triphenylphosphine)Palladium (0.5 g, 0.45 mmol) and heated withstirring at 70° C. for 68 h. The reaction was diluted with water (60 mL)and extracted with ethyl acetate (3×25 mL). The organic layers werecombined washed with water (25 mL), brine (25 mL), dried, filtered, andconcentrated in vacuo to dryness. The residue obtained was purified byflash column chromatography (silica gel 40 g, eluting with 0-100% [9:1]of EtOAc: MeOH in hexane) to give 89a (0.615 g, 33%) as a brown solid.¹H NMR (300 MHz, DMSO-d₆) δ 7.93 (s, 1H), 7.84 (s, 1H), 7.35 (s, 2H),6.86 (s, 114), 5.56 (s, 1H), 5.00 (t, J=5.8 Hz, 1H), 4.39 (d, J=2.4 Hz,1H), 4.10-4.00 (m, 1H), 3.73 (d, J=4.6 Hz, 3H), 3.59 (t, J=5.4 Hz, 2H),2.07 (d, J=1.2 Hz, 3H), 1.56 (s, 3H), 1.34 (s, 3H), 1.14 (s, 3H).b. To a freshly prepared solution of sodium methoxide (1.57 mL, 0.1 M)in methanol (14 mL) was added 89a (0.657 g, 1.57 mmol) and heated withstirring at reflux temperature overnight. The reaction mixture wasneutralized with glacial acetic acid (0.3 mL) and concentrated in vacuoto dryness. The residue obtained was purified by flash columnchromatography (silica gel 12 g, eluting with 0-100% [9:1] of EtOAc:MeOH in hexane) to give 89b (0.165 g, 27%) as a yellow solid.

Example 5 Synthesis of 90c

To a solution of 90b (0.050 g, 0.13 mmol) in methanol (0.5 mL) was addedaqueous 1 N HCl (0.5 mL) and stirred at room temperature for 48 h. Thereaction mixture was concentrated in vacuo to dryness. The solidobtained was triturated with ether, collected by filtration, washed withether and dried in vacuo at acetone reflux temperature to furnish 90c(0.008 g, 18%) as an off white solid; mp 234° C. ¹H NMR (300 MHz,DMSO-d₆) δ 11.33-10.90 (m, 1H), 8.05 (s, 1H), 7.13 (s, 1H), 5.80 (d,J=1.2 Hz, 1H), 5.34 (s, 1H), 4.99 (s, 3H), 3.83-3.70 (m, 3H), 3.61 (dd,J=4.2, 12.5 Hz, 1H), 2.20 (d, J=1.1 Hz, 3H), 0.84 (s, 3H); MS (ES)344.9.

Intermediate 90b was prepared as follows:

a. To a solution of 40m (1.3 g, 3 mmol) in DMF (25 mL) was added copperiodide (110 mg, 0.6 mmol), methyl crotonate (6.36 ml, 60 mmol),triethylamine (0.84 mL, 6 mmol) and tetrakis(triphenylphosphine)palladium (0.350 g, 0.3 mmol) and heated at 70° C. for 48 h. Thereaction was diluted with water (75 mL) and extracted with ethyl acetate(2×25 mL). The organic layers were combined, washed with water (2×25mL), brine (25 mL), dried, filtered, and concentrated in vacuo todryness. The residue obtained was purified by flash columnchromatography (silica gel 40 g, eluting with 0-100% [9:1] of EtOAc:MeOH in hexane) to give 90a (0.565 g, 46%). ¹H NMR (300 MHz, DMSO-d₆) δ7.95 (d, J=2.8 Hz, 2H), 6.87 (s, 1H), 5.78 (d, J=1.3 Hz, 1H), 5.56 (s,114), 4.98 (t, J=5.8 Hz, 1H), 4.39 (d, J=2.5 Hz, 1H), 4.07-3.98 (m, 1H),3.65 (s, 3H), 3.59 (t, J=5.4 Hz, 2H), 3.33 (s, 1H), 2.55 (d, J=1.1 Hz,3H), 1.56 (s, 3H), 1.34 (s, 3H), 1.15 (s, 3H).b. To a freshly prepared solution of sodium methoxide (0.67 mL, 0.1 M)in methanol (6 mL) was added 90a (0.280 g, 0.67 mmol) and heated withstirring at reflux overnight. The reaction mixture was concentrated invacuo and the residue obtained was purified by flash columnchromatography (silica gel 4 g, eluting with 0-100% CMA 80 inchloroform) to give 90b (0.100 g, 39%) as a yellow solid; mp 152° C. ¹HNMR (300 MHz, DMSO-d₆) δ 11.14 (s, 1H), 8.06 (s, 1H), 6.97 (s, 1H), 5.82(s, 1H), 5.47 (s, 1H), 5.01 (t, J=5.9 Hz, 1H), 4.41 (d, J=2.5 Hz, 1H),4.11-4.01 (m, 1H), 3.62 (t, J=5.3 Hz, 2H), 2.22 (d, J=1.1 Hz, 3H), 1.56(s, 3H), 1.34 (s, 3H), 1.12 (s, 3H); MS (ES) 384.9.

Example 6 Synthesis of 91b

To a solution of tricyclic product 91a (20 mg, 0.05 mmol) in methanol(0.5 mL) was added aqueous 1 N HCl (0.5 mL) and stirred at roomtemperature overnight. The reaction mixture was concentrated in vacuo todryness to furnish 91b (19 mg, 100%) as a white solid; mp 59-64° C. NMR(300 MHz, DMSO-d₆) δ 8.73-8.30 (m, 21-1), 8.02 (s, 1H), 6.79 (s, 1H),5.32 (s, 1H), 4.06-3.84 (m, 3H), 3.75 (d, J=11.7 Hz, 31-1), 3.63 (d,J=8.8 Hz, 2H), 3.14 (d, J=7.3 Hz, 211), 0.77 (s, 3H); MS (ES) 332.9.

Intermediate 91a was prepared as follows.

To a solution of tricyclic product 40o (100 mg, 0.27 mmol) in methanol(100 mL) was added platinum oxide (50 mg) and hydrogenated at 50 psi for3 days. The catalyst was removed by filtration through a pad of Celiteand the filtrate concentrated in vacuo to give crude product.

The crude residue was purified by flash column chromatography (silicagel 4 g, eluting with CHCl₃/CMA-80, 0-100%) to furnish crude 91a (64mgs). The crude material was recrystallized from methanol (2 mL) tofurnish pure 91a (25 mg, 25%) as a white solid. ¹H NMR (300 MHz,DMSO-d₆) δ 11.02 (s, 1H), 8.17 (s, 1H), 6.78 (s, 1H), 5.58 (s, 1H), 5.00(s, 1H), 4.40 (s, 1H), 4.05 (s, 1H), 3.58 (s, 2H), 3.02 (s, 2H), 2.91(s, 2H), 1.56 (s, 3H), 1.34 (s, 3H), 1.14 (s, 3H); MS (ES⁺) 375.0, (ES)373.3.

Example 7 Synthesis of 92c

To a solution of tricyclic product 92b (220 mg, 0.59 mmol) in methanol(4 mL) was added aqueous 1 N HCl (4 mL) and stirred at room temperatureovernight. The reaction mixture was concentrated in vacuo to dryness.The residue obtained was triturated with ether and the solid obtainedwas collected by filtration, washed with ether and dried in vacuo atacetone reflux temperature to furnish 92c (145 mg, 74%) as a mustardsolid; mp 152-159° C. ¹H NMR (300 MHz, DMSO-d₆) δ 12.60 (s, 1H), 9.76(s, 1H), 9.27 (s, 1H), 8.02 (s, 1H), 7.55 (d, J=11.6 Hz, 1H), 7.13 (s,1H), 6.39 (d, J=11.6 Hz, 1H), 5.23 (s, 1H), 4.99-4.20 (m, 3H), 3.77 (d,J=10.1 Hz, 2H), 3.70-3.57 (m, 2H), 0.87 (s, 3H); MS (ES⁺) 332.0, (ES)329.9.

Intermediate 92b was prepared as follows.

a. To a solution of 40m (2.23 g, 4.99 mmol) in DMF (70 mL) was addedcopper iodide (380 mg, 1.99 mmol), triethylamine (3 mL, 21.8 mmol) andtetrakis(triphenylphosphine) palladium (1.15 g, 1 mmol). To thesuspension was added acrylonitrile (14.3 ml, 217 mmol) in 4 portionsover a period of 3 h and heated with stirring at 70° C. for 3 days. Thereaction was diluted with water (210 mL) and extracted with ethylacetate (3×70 mL). The organic layers were combined, washed with water(70 mL), brine (70 mL) dried, filtered, and concentrated in vacuo todryness. The residue obtained was purified by flash columnchromatography (silica gel, 110 g, eluting with 0-100% [9:1] of EtOAc:MeOH in hexane) to give 92a (619 mg, 33%) as a mustard-colored solid; mp238° C. ¹H NMR (300 MHz, DMSO-d₆) δ 8.15 (d, J=15.9 Hz, 1H), 7.74 (s,2H), 7.42 (s, 1H), 7.20 (s, 1H), 6.19 (d, J=15.7 Hz, 1H), 5.51 (s, 1H),4.96 (t, J=5.8 Hz, 1H), 4.39 (d, J=2.4 Hz, 1H), 4.03 (d, J=2.4 Hz, 1H),3.66-3.55 (m, 2H), 1.55 (s, 3H), 1.33 (s, 3H), 1.12 (s, 3H); IR (KBr)2209 cm⁻¹; MS (ES) 370.1.8.

To a freshly prepared solution of sodium methoxide (36 mg sodium in 1.6ml methanol, 0.1 M) was added 92a (0.58 g, 1.56 mmol) and heated withstirring at reflux for 4 h and then at room temperature overnight. Thereaction mixture was neutralized with glacial acetic acid (0.094 mL) andconcentrated in vacuo to dryness. The residue obtained was purified byflash column chromatography (silica gel 12 g, eluting with CHCl₃/CMA-80,0-100%) to furnish 92b (265 mg, 44%) as a rust solid; mp 112-114° C. ¹HNMR (300 MHz, DMSO-d₆) δ 8.05 (s, 1H), 7.96 (s, 1H), 7.68 (s, 1H), 6.99(d, J=11.4 Hz, 1H), 6.60 (s, 1H), 5.73 (d, J=11.5 Hz, 1H), 5.34 (s, 1H),4.98 (t, J=5.7 Hz, 1H), 4.37 (d, J=2.4 Hz, 1H), 4.03-3.98 (m, 1H),3.64-3.48 (m, 2H), 1.52 (s, 3H), 1.33 (s, 3H), 1.12 (s, 3H); MS (ES⁺)372.1, (ES) 369.9.

Example 8 Synthesis of 93f

To a suspension of 93e (310 mg, 0.54 mmol) in MeOH was added 1N aqueousHCl (1.8 mL) Pd/C (10%, 100 mg) and hydrogenated at 60 psi for 25 h. Thereaction mixture was filtered and the filtrate was concentrated invacuo. The residue obtained was purified by flash column chromatography(silica gel, 30 g, eluting with chloroform/CMA80, 1:0 to 1:1) to furnish93f (137 mg, 83%) as a white solid; mp: 254.2° C. ¹H NMR (300 MHz,DMSO-d₆) δ 7.96 (s, 1H), 7.78 (s, 1H), 6.50 (s, 1H), 5.28 (s, 1H), 4.92(d, J=6.7 Hz, 1H), 4.76 (t, J=5.4 Hz, 1H), 4.71 (s, 1H), 3.80-3.67 (m,3H), 3.65-3.50 (m, 314), 2.95-2.85 (m, 2H), 0.83 (s, 3H); MS (ES⁺):307.1.

Intermediate 93e was prepared as follows.

a. To a solution of 42a (27.85 g, 44.23 mmol) in pyridine (400 mL) wasadded 4-methoxytriphenylmethyl chloride (56.74 g, 178.24 mmol) andheated with stirring at 70° C. for 16 h. The reaction mixture wasdiluted with EtOAc (1.5 L), washed with water (2×700 mL) and brine (500mL), dried, filtered, and concentrated. The residue was purified byflash column chromatography (silica gel eluting with hexanes/EtOAc, 1:0to 4:1) to give 93a (28.38 g, 71%) as a light yellow solid; mp 78.6° C.¹H NMR (300 MHz, DMSO-d₆): δ 7.91 (s, 1H), 7.63 (s, 1H), 7.45-7.12 (m,27H), 6.96 (s, 1H), 6.87 (d, J=8.9 Hz, 2H), 5.56 (s, 1H), 4.74-4.50 (m,6H), 4.20-4.12 (m, 1H), 4.02 (d, J=8.5 Hz, 1H), 3.87-3.64 (m, 2H), 3.71(s, 3H), 1.05 (s, 3H).b. To a solution of 93a, (26.1 g, 28.94 mmol) in DME (500 mL) was addedpotassium vinyltrifluoroborate (7.2 g, 53.75 mmol), NaHCO₃ (7.2 g, 85.70mmol), Pd(PPh₃)₂Cl₂ (1.4 g, 98%, 1.99 mmol), H₂O (65 mL) and refluxedfor 6 h. The reaction mixture was diluted with water (500 mL) andextracted with EtOAc (1.8 L and 0.5 L). The organic layers were combinedand washed with brine (500 mL), dried, filtered, and concentrated invacuo. The residue was purified by flash column chromatography (silicagel eluting with hexanes/EtOAc, 1:0 to 6:1) to furnish 93b (18.3 g, 74%)as a light yellow solid; mp 79.7° C. ¹H NMR (300 MHz, DMSO-d₆) δ 7.56(s, 1H), 7.44-7.12 (m, 28H), 7.01 (dd, J=17.2, 11.0 Hz, 1H), 6.93 (s,1H), 6.84 (d, J=8.8 Hz, 2H), 5.57 (s, 1H), 5.31 (d, J=17.2 Hz, 1H), 5.16(d, J=11.0 Hz, 1H), 4.76-4.52 (m, 6H), 4.22-4.13 (m, 1H), 4.04 (d, J=8.4Hz, 1H), 3.88-3.70 (m, 2H), 3.71 (s, 3H), 1.05 (s, 3H); MS (ES): 847.6.c. To a cold (ice water bath) solution of 93b (20.5 g, 24.15 mmol) inTHF (90 mL) was added dropwise borane dimethyl sulfide solution (2M inTHF, 9.5 mL) and stirred at room temperature for 4 h. The reactionmixture was quenched with ethanol (19 mL), aqueous 3N NaOH (6.0 mL), andcooled with ice/water. To the cold reaction mixture was added hydrogenperoxide (30% in water, 6 mL) and heated at reflux for 1 h. The reactionmixture was cooled to room temperature, diluted with ethyl acetate (1L),washed with water (2×500 mL), brine (300 ml), dried and concentrated invacuo. The residue obtained was purified by flash column chromatography(silica gel, eluting with ethyl acetate in hexane 1:0 to 2:1) to give93c (11.17 g, 53%) as a yellow solid. ¹H NMR (300 MHz, DMSO-d₆) δ 8.95(s, 1H), 7.45 (s, 1H), 7.42-7.22 (m, 27H), 6.81 (d, J=9.0 Hz, 2H), 6.62(s, 1H), 5.57 (s, 1H), 5.51 (t, J=3.7 Hz, 1H), 4.76-4.48 (m, 6H),4.20-4.10 (m, 1H), 4.04 (d, J=8.4 Hz, 1H), 3.91-3.66 (m, 2H), 3.71 (s,3H), 3.58-3.46 (m, 2H), 2.97-2.86 (s, 2H), 1.03 (s, 3H).d. To a solution of 93c (1.0 g, 1.15 mmol) and triphenylphosphine (610mg, 2.30 mmol) in 1,4-dioxane (15 mL) was added dropwise a solution ofDIAD (0.5 mL, 95%, 2.41 mmol) in 1,4-dioxane (2.5 mL) and stirred atroom temperature for 16 h. The reaction mixture was concentrated invacuo and the residue obtained was purified by flash columnchromatography (silica gel 50 g, eluting with ethyl acetate in hexane1:0 to 4:1) to give 93d (730 mg, 75%) as a white solid. ¹H NMR (300 MHz,DMSO-d₆): δ 7.68 (s, 1H), 7.49-7.15 (m, 27H), 6.86 (d, J=9.0 Hz, 2H),6.59 (s, 1H), 5.53 (s, 1H), 4.80-4.45 (m, 6H), 4.22-4.10 (m, 1H), 4.02(d, J=7.9 Hz, 1H), 3.86-3.64 (m, 2H), 3.72 (s, 3H), 3.60-3.34 (m, 2H),3.18-2.92 (m, 2H), 1.08 (s, 3H); MS (ES⁺): 671.1 (M+Na).e. To a solution of 93d (618 mg, 0.73 mmol) in acetonitrile (35 mL) wasadded aqueous 1N HCl (3.5 mL) and stirred at room temperature for 17 h.The reaction mixture was neutralized with aqueous 0.5 N NaOH, dilutedwith water (50 mL), and concentrated in vacuo to remove acetonitrile.The aqueous layer was extracted with CHCl₃/MeOH (5:1, 100 mL and 50 mL).The combined organic extracts were dried, filtered and concentrated invacuo. The residue obtained was purified by flash column chromatography(silica gel 30 g, eluting with hexane/ethyl acetate/methanol, 1:1:0 to1:1:0.1) to give 93e (362 mg, 86%) as a white solid. ¹H NMR (300 MHz,DMSO-d₆) δ 8.01 (s, 1H), 7.81 (s, 1H), 7.41-7.27 (m, 15H), 6.53 (s, 1H),5.55 (s, 1H), 4.77-4.49 (m, 6H), 4.26-4.12 (m, 1H), 4.04 (d, J=8.1 Hz,114), 3.85-3.65 (m, 2H), 3.60-3.48 (m, 2H), 2.83 (t, J=6.5 Hz, 2H), 1.10(s, 3H); MS (ES⁺): 577.1.

Example 9 Synthesis of 94

To a suspension of 40p (33 mg, 0.1 mmol) in trimethylphosphate (1 mL) at0° C. was added phosphorus oxychloride (19 μL, 0.21 mmol) and stirred at0° C. for 1 h. The reaction mixture was treated with n-tributylamine (70μL, 0.29 mmol), acetonitrile (100 μL), tributylammonium pyrophosphate(H₄P₂O₇.1.6 n-Bu₃N, 190 mg, 0.40 mmol) and stirred at room temperaturefor 0.5 h. The reaction mixture was quenched with 1M TEAB buffer (5 mL,pre-cooled with ice/water, pH=8.0), diluted with water (20 mL), andwashed with dichloromethane (2×15 mL). The aqueous solution wasconcentrated in vacuo to remove traces of CH₂Cl₂ and purified by DEAEion exchange column chromatography with a linear gradient of TEAB buffer(1M TEAB buffer, pH=8.0/H₂O, 0:1 to 1:0, total volume: 500 mL). Thefractions containing the desired triphosphate were combined andconcentrated. The residue was re-dissolved in H₂O and purified byHPLC(CH₃CN/0.1 M TEAB buffer, pH=8.0, 0-30 min; 0-35% CH₃CN; monitoringat 238 nM) to give 94 (t_(R)=18.7 min). Fractions containing 94 wereconcentrated and re-dissolved in 2 mL of H₂O and the concentration of 94was measured to be 0.34 mM (yield: 0.7%) by UV (240 nm, ε=58,000 M⁻¹cm⁻¹). ¹H NMR (300 MHz, D₂O) δ 7.79 (s, 1H), 7.19 (d, J=12.0 Hz, 1H),7.02 (s, 1H), 5.78 (d, J=12.0 Hz, 1H), 5.46 (s, 1H), 4.04 (s, 2H),4.50-3.50 (m, 2H), 0.91 (s, 3H). ³¹P NMR (121 MHz, D₂O): δ −8.8 (1P),−11.0 (1P), −22.3 (1P), MS (ES): 570.9 (M−1).

Example 10 Synthesis of 95

To a suspension of 95e (64 mg, 0.2 mmol) in trimethylphosphate (2 mL) at0° C. was added phosphorus oxychloride (37 μL, 0.4 mmol) and stirred at0° C. for 1 h. The reaction mixture was treated with n-tributylamine(150 μL, 0.62 mmol), acetonitrile (200 μL), tributylammoniumpyrophosphate (H₄P₂O₇.1.6 n-Bu₃N, 380 mg, 0.8 mmol) and stirred at roomtemperature for 0.5 h. The reaction mixture was quenched with 1M TEABbuffer (10 mL, pre-cooled with ice water, pH=8.0), diluted with water(20 mL), and washed with dichloromethane (2×15 mL). The aqueous phasewas concentrated in vacuo to remove the trace of CH₂Cl₂ and purified byDEAE ion exchange column chromatography with a linear gradient of TEABbuffer (1M TEAB buffer, pH=8.0/H₂O, 0:1 to 1:0, total: 500 mL). Thefractions containing the desired triphosphate were combined andconcentrated. The residue was re-dissolved in H₂O and purified byHPLC(CH₃CN/0.1 M TEAB buffer, pH=8.0, 0-40 min, 0-35% CH₃CN; monitoringat 244 nm) to give 95 (t_(R)=17.2 min). Fractions containing 95 wereconcentrated and re-dissolved in 2 mL of H₂O and the concentration of 95was measured to be 9.8 mM (yield: 10%) by UV (280 nm, ε=6,400 M⁻¹ cm⁻¹).¹H NMR (300 MHz, D₂O) δ 7.53 (s, 1H), 6.40 (s, 1H), 5.31 (s, 1H),4.32-4.00 (m, 4H), 0.93 (s, 3H); ³¹P NMR (D₂O) δ −10.69 (d, J=19.4 Hz,1P), −11.26 (d, J=20.6 Hz, 1P), −23.24 (t, J=19.4 Hz, 1P). MS (ES):560.1 (M−1).

Example 11

The following illustrate representative pharmaceutical dosage forms,containing a compound of Formula I, or a pharmaceutically acceptablesalt or prodrug thereof (‘Compound X’), for therapeutic or prophylacticuse in humans.

(i) Tablet 1 mg/tablet Compound X = 100.0 Lactose 77.5 Povidone 15.0Croscarmellose sodium 12.0 Microcrystalline cellulose 92.5 Magnesiumstearate 3.0 300.0

(ii) Tablet 2 mg/tablet Compound X = 20.0 Microcrystalline cellulose410.0 Starch 50.0 Sodium starch glycolate 15.0 Magnesium stearate 5.0500.0

(iii) Capsule mg/capsule Compound X = 10.0 Colloidal silicon dioxide 1.5Lactose 465.5 Pregelatinized starch 120.0 Magnesium stearate 3.0 600.0

(iv) Injection 1 (1 mg/ml) mg/ml Compound X = (free acid form) 1.0Dibasic sodium phosphate 12.0 Monobasic sodium phosphate 0.7 Sodiumchloride 4.5 1.0 N Sodium hydroxide solution (pH adjustment to 7.0-7.5)q.s. Water for injection q.s. ad 1 mL

(v) Injection 2 (10 mg/ml) mg/ml Compound X = (free acid form) 10.0Monobasic sodium phosphate 0.3 Dibasic sodium phosphate 1.1 Polyethyleneglycol 400 200.0 01 N Sodium hydroxide solution (pH adjustment to7.0-7.5) q.s. Water for injection q.s. ad 1 mL

(vi) Aerosol mg/can Compound X = 20.0 Oleic acid 10.0Trichloromonofluoromethane 5,000.0 Dichlorodifluoromethane 10,000.0Dichlorotetrafluoroethane 5,000.0

The above formulations may be obtained by conventional procedures wellknown in the pharmaceutical art.

All publications, patents, and patent documents are incorporated byreference herein, as though individually incorporated by reference. Theinvention has been described with reference to various specific andpreferred embodiments and techniques. However, it should be understoodthat many variations and modifications may be made while remainingwithin the spirit and scope of the invention.

1. A compound of formula I:

wherein; B represents a 5, 6, 7 or 8 membered carbocyclic orheterocyclic ring comprising one or more double bonds, wherein B isoptionally substituted with one or more oxo, thioxo, NR_(c)R_(d), F, Cl,Br, I, OR_(z), SR_(z), alkyl, C≡N, C≡C—R, N₃ or SO₂R′; wherein: R is H,alkyl or aryl; R′ is OH, NH₂ or alkyl; R¹ is H, NR_(a)R_(b), Cl, F,OR_(a), SR_(a), NHCOR_(a), NHSO₂R_(a), NHCONHR_(a), CN, alkyl, aryl,ONR_(a)R_(b), or NR_(a)C(O)OR_(b); R² is a nucleoside sugar group; W³ isabsent, alkyl, or H; R_(a) and R_(b) are independently selected from thegroup consisting of H, alkyl, substituted alkyl, alkenyl, substitutedalkenyl, alkynyl, substituted alkynyl, cycloalkyl, heterocyclic, aryl,substituted aryl, acyl, substituted acyl, SO₂-alkyl, amino, substitutedamino, and NO; or R_(e) and R_(b) together with the nitrogen to whichthey are attached form a pyrrolidino, piperidino, piperazino, azetidino,morpholino, or thiomorpholino ring; R_(c) and R_(d) are independentlyselected from the group consisting of H, alkyl, substituted alkyl,alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl,acyl, substituted acyl and SO₂-alkyl; or R_(c) and R_(d) together withthe nitrogen to which they are attached form a pyrrolidino, piperidino,piperazino, azetidino, morpholino, or thiomorpholino ring; and eachR_(z) is independently selected from the group consisting of H, alkyl,substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substitutedalkynyl, cycloalkyl, acyl and substituted acyl; or a pharmaceuticallyacceptable salt or prodrug thereof.
 2. The compound of claim 1 whereinthe compound of formula I is a compound of formula II:

wherein; B represents a 5, 6, 7 or 8 membered ring comprising one ormore heteratoms and one or more double bonds, wherein B is optionallysubstituted with one or more oxo, thioxo, NR_(c)R_(d), F, Cl, Br, I,OR_(z), SR_(z), alkyl, C≡N, C≡C—R, N₃ or SO₂R′; wherein: R is H, alkylor aryl; R′ is OH, NH₂ or alkyl; R¹ is H, NR_(a)R_(b), Cl, F, OR_(a),SR_(a), NHCOR_(a), NHSO₂R_(a), NHCONHR_(a), CN, alkyl, aryl,ONR_(a)R_(b), or NR_(a)C(O)OR_(b); R² is a nucleoside sugar group; W³ isabsent, alkyl, or H; R_(a) and R_(b) are independently selected from thegroup consisting of H, alkyl, substituted alkyl, alkenyl, substitutedalkenyl, alkynyl, substituted alkynyl, cycloalkyl, heterocyclic, aryl,substituted aryl, acyl, substituted acyl, SO₂-alkyl, amino, substitutedamino, and NO; or R_(a) and R_(b) together with the nitrogen to whichthey are attached form a pyrrolidino, piperidino, piperazino, azetidino,morpholino, or thiomorpholino ring; R_(c) and R_(d) are independentlyselected from the group consisting of H, alkyl, substituted alkyl,alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl,acyl, substituted acyl and SO₂-alkyl; or R_(c) and R_(d) together withthe nitrogen to which they are attached form a pyrrolidino, piperidino,piperazino, azetidino, morpholino, or thiomorpholino ring; and eachR_(z) is independently selected from the group consisting of H, alkyl,substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substitutedalkynyl, cycloalkyl, acyl and substituted acyl; or a pharmaceuticallyacceptable salt or prodrug thereof.
 3. The compound of claim 2 whereinW³ is absent or H.
 4. A compound of claim 1 which is a compound offormula III:

wherein: each b, c and d is independently selected from a single anddouble bond provided that when b is a double bond, c is single bond,when c is a double bond, b and d are single bonds and when d is a doublebond c is a single bond; or d is absent when W² is absent; and W² and dare not absent, when bNW³ is absent; W is C═R_(e), CH₂, CR_(g) or O,provided that when W is C═R_(e), CH₂ or O, b and c are single bonds, orc is a single bond and bNW³ is absent; and provided when W is CR_(g),one of b or c is a double bond, or bNW³ is absent and c is a doublebond; R_(e) is O or S; R_(g) is H, NR_(c)R_(d), OR_(z) or SR_(z); W¹ isC═R_(h), CR_(i)R_(i′), N, NR_(n), CR_(j) or O provided that when W¹ isC═R_(h), CR_(i)R_(i), NR_(n) or O, c and d are single bonds or c is asingle bond and W²d is absent; and provided when W¹ is CR_(j) or N oneof c or d is a double bond or W2d is absent and c is a double bond;R_(h) is O or S; R_(i) and R_(i′) are H, CH₃, NH₂ or Br; R_(j) is CH₃,NH₂, or H; W² is C═R_(k), (CR_(l)R_(l′))_(p′), CR_(m), O, NR_(s), absentor N provided that when W² is C═R_(k), CR_(l)R_(l′), O, or NR_(s) d is asingle bond; when W² is N or CR_(m) d is a double bond; and providedwhen W² is absent, d is absent; R_(k) is O or S; R_(l) and R_(l′) are H,CH₃, OCH₃, NH₂ or SCH₃; p′ is 1 or 2; R_(m) is H, NR_(c)R_(d), F, Cl,Br, I, OR_(z), SR_(z), alkyl, C≡N, C≡R, N₃ or SO₂R′; R_(n) is H, alkyl,or NR_(q)R_(r) wherein each R_(q) and R_(r) is H or alkyl; R_(s) is H,CH₃, or NH₂; and W³ is absent, H or alkyl; provided that when W³ isabsent b is a double bond; or a pharmaceutically acceptable salt orprodrug thereof.
 5. A compound of claim 1 which is a compound of formulaIV:

wherein: each b, c and d is independently selected from a single ordouble bond provided that when b is a double bond, c is single bond,when c is a double bond, b and d are single bonds and when d is a doublebond c is a single bond; or d is absent when W² is absent; W is C═R_(e),CR_(f)R_(f), CR_(g) or O, provided that when W is C═R_(e), CR_(f)R_(f)or O, b and c are single bonds and when W is CR_(g), one of b or c is adouble bond; R_(e) is O or S; R_(f) is H; R_(g) is H, NR_(c)R_(d),OR_(z) or SR_(z); W¹ is C═R_(h), CR_(i)R_(i′), NH, CR_(j) or O providedthat when W¹ is C═R_(h), CR_(i)R_(i), or O, c and d are single bonds;when W¹ is CR_(j), one of c or d is a double bond; and when W¹ is NH, Wis not O and W² is not O, NH, or N; R_(h) is O or S; R_(i) and R_(i′)are H, CH₃ or Br; R_(j) is CH₃ or H; W² is C═R_(k), (CR_(l)R_(l′))_(p′),CR_(m), O, NH, absent, or N provided that when W² is C═R_(k),CR_(l)R_(l′), CR_(m), O, or NH d is a single bond; when W² is N orCR_(m) d is a double bond; or when W² is absent, d is absent; R_(k) is Oor S; R_(l) and R_(l′) are H, CH₃, OCH₃ or SCH₃; p′ is 1 or 2; R_(m) isH, NR_(c)R_(d), F, Cl, Br, I, OR_(z), SR_(z), alkyl, C≡N, C≡C—R, N₃ orSO₂R′; and W³ is absent, H or alkyl; provided that when W³ is absent bis a double bond; or a pharmaceutically acceptable salt or prodrugthereof.
 6. The compound of formula IV as described in claim 5 wherein:each b, c and d is independently selected from a single or double bondprovided that when b is a double bond, c is single bond, when c is adouble bond, b and d are single bonds and when d is a double bond c is asingle bond; W is C═R_(e), CR_(f)R_(f), CR_(g) or O, provided that whenW is C═R_(e), CR_(f)R_(f) or O, b and c are single bonds and when W isCR_(g), one of b or c is a double bond; R_(e) is O or S; R_(f) is H;R_(g) is H, NR_(c)R_(d), OR_(z) or SR_(z); W¹ is C═R_(h), CR_(i)CR_(i′),CR_(j) or O provided that when W¹ is C═R_(h), CR_(i)R_(i′), or O, c andd are single bonds and when W¹ is CR_(j), one of c or d is a doublebond; R_(h) is O or S; R_(i) and R_(i′) are H, CH₃ or Br; R_(j) is CH₃or H; W² is C═R_(k), (CR_(l)R_(l′))_(p′), CR_(m), O, NH or N providedthat when W² is C═R_(k), CR_(l)R_(l′), CR_(m), O, or NH d is a singlebond and when W² is N or CR_(m) d is a double bond; R_(k) is O or S;R_(l) and R_(l′) are H, CH₃, OCH₃ or SCH₃; p′ is 1 or 2; R_(m) is H,NR_(c)R_(d), F, Cl, Br, I, OR_(z), SR_(z), alkyl, C≡N, C≡C—R, N₃ orSO₂R′; and W³ is absent or H, provided that when W³ is absent b is adouble bond; or a pharmaceutically acceptable salt or prodrug thereof.7. The compound of claim 1 wherein the compound of formula I is acompound of formula V:

wherein: each of b and c is independently selected from a single ordouble bond provided that when b is a double bond, c is single bond andwhen c is a double bond b is a single bond; W is C═R_(e), CR_(f)R_(f),CR_(g) or O, provided that when W is C═R_(e), CR_(f)R_(f) or O, b and care single bonds and when W is CR_(g), one of b or c is a double bond;R_(e) is O or S; R_(f) is H; R_(g) is H, NR_(c)R_(d), OR_(z) or SR_(z);W¹ is C═R_(h), CR_(i)R_(i′), NH, CR_(j) or O provided that when W¹ isC═R_(h), CR_(i)R_(i), or O, c is a single bond; when W¹ is CR_(j), c isa double bond; and when W¹ is NH, W is not O; R_(h) is O or S; R_(i) andR_(i′) are each independently H, CH₃ or Br; R_(j) is CH₃ or H; and W³ isabsent, H, or alkyl, provided that when W³ is absent b is a double bond;or a pharmaceutically acceptable salt or prodrug thereof.
 8. A compoundof claim 1 which is a compound of formula I-9:

wherein: X¹ is O, S, or two hydrogens; X² is O, S, or two hydrogens; X³is O or S; X⁴ is O, S, or two hydrogens; X⁵ is O, S, or two hydrogens;X⁸ is H, NH₂, OCH₃ or SCH₃; Y¹ is H, OH, NH₂, NHCH₃, N(CH₃)₂, F, Cl, Br,I, alkoxy, alkyl SCH₃, C≡N, C≡C—R, N₃ or SO₂R′; Y² is H, CH₃, OCH₃ orSCH₃; Y³ is O or S; Y⁴ is O, S, or two hydrogens; Z¹ is H or CH₃; Z² isH, CH₃ or Br; and t is 1 or 2; or a pharmaceutically acceptable salt orprodrug thereof.
 9. The compound of claim 1 wherein R¹ is H orNR_(a)R_(b).
 10. The compound of claim 1 which is selected from,

or a pharmaceutically acceptable salt or prodrug thereof.
 11. Thecompound of claim 1 wherein R² is ribose, 2-methylribose, 2-deoxyribose;2-deoxy-2-fluororibose; arabinose; 2-deoxy-2-fluoroarabinose;2,3-dideoxyribose; 2,3-dideoxy-2-fluoroarabinose;2,3-dideoxy-3-fluororibose; 2,3-dideoxy-2,3-didehydroribose;2,3-dideoxy-3-azidoribose; 2,3-dideoxy-3-thiaribose; or2,3-dideoxy-3-oxaribose; or a pharmaceutically acceptable salt orprodrug thereof.
 12. The compound of claim 1 wherein R² is thioribose,2-deoxythioribose; 2-deoxy-2-fluorothioribose; thioarabinose;2-deoxy-2-fluorothioarabinose; 2,3-dideoxythioribose;2,3-dideoxy-2-fluorothioarabinose; 2,3-dideoxy-3-fluorothioribose;2,3-dideoxy-2,3-didehydrothioribose; or 2,3-dideoxy-3-azidothioribose;or a pharmaceutically acceptable salt or prodrug thereof.
 13. Thecompound of claim 1 wherein R² is 4-hydroxymethyl-cyclopent-2-ene;2,3-dihydroxy-4-hydroxymethylcyclopent-4-ene;3-hydroxy-4-hydroxymethylcyclopentane;2-hydroxy-4-hydroxymethylcyclopentene;2-fluoro-3-hydroxy-4-hydroxymethylcyclopentane;2,3-dihydroxy-4-hydroxymethyl-5-methylenecyclopentane;4-hydroxymethylcyclopentane, 2,3-dihydroxy-4-hydroxymethylcyclopentane;or 2,3-dihydroxymethylcyclobutane; or a pharmaceutically acceptable saltor prodrug thereof.
 14. The compound of claim 1 wherein R² is4-hydroxymethyl-pyrrolidine; 2,3-dihydroxy-4-hydroxymethylpyrrolidine;2/3-hydroxy-4-hydroxymethylpyrrolidine;2-fluoro-3-hydroxy-4-hydroxymethylpyrrolidine; or3-fluoro-2-hydroxy-4-hydroxymethyl-pyrrolidine; or a pharmaceuticallyacceptable salt or prodrug thereof.
 15. The compound of claim 1 whichis:

or a pharmaceutically acceptable salt or prodrug thereof.
 16. Thecompound of claim 1 which is:

or a pharmaceutically acceptable salt or prodrug thereof.
 17. Thecompound of claim 1 which is:

or a pharmaceutically acceptable salt or prodrug thereof.
 18. Thecompound of claim 1 which is:

or a pharmaceutically acceptable salt or prodrug thereof.
 19. Thecompound of claim 1 which is:

or a pharmaceutically acceptable salt or prodrug thereof.
 20. Thecompound of claim 1 which is a prodrug.
 21. A pharmaceutical compositioncomprising a compound as described in claim 1 and a pharmaceuticallyacceptable carrier.
 22. A method for treating a viral infection in ananimal comprising administering to the animal an effective amount of acompound as described in claim 1, or a composition as described in claim21.
 23. A method for treating cancer in an animal comprisingadministering to the animal an effective amount of a compound asdescribed in claim 1, or a composition as described in claim
 21. 24. Amethod for inhibiting a viral RNA or DNA polymerase comprisingcontacting the polymerase in vitro or in vivo with an effectiveinhibitory amount of a compound as described in claim 1, or acomposition as described in claim 21.